Novel muscarinic receptor agonists

ABSTRACT

This invention relates to a novel class of partial or full muscarinic receptor agonists intermediates for their preparation, and pharmaceutical compositions and methods of use for the treatment or prevention of diseases the treatment or prevention of which is mediated by muscarinic receptor agonism

BACKGROUND OF THE INVENTION

[0001] This invention relates to a novel class of partial or fullmuscarinic receptor agonists, intermediates for their preparation, andpharmaceutical compositions and methods of use for the treatment orprevention of diseases the treatment or prevention of which is mediatedby muscarinic receptor agonism. Some compounds described exhibitmuscarinic antagonist activity or mixed agonist/antagonist activity andthereby are useful for treatment or prevention of diseases or syndromescharacterized by excessive cholinergic activity. Muscarinic receptorsare pre- and post-synaptic receptors in the cholinergic neurotransmittersystem. Disruption of the cholinergic neurotransmitter system has beenimplicated in age related central nervous system (CNS) dysfunction.Muscarinic receptor agonists are believed, by those of ordinary skill inthe art, to be useful in treating or preventing age related CNSdysfunction, such as cognitive decline and Alzheimer's disease thatresults from disruption of the cholinergic neurotransmitter system.

[0002] Specific evidence for the role of the cholinergicneurotransmitter system in age related CNS dysfunction has been reportedby Bartus, R. T. et al., in The Cholinergic Hypothesis of GeriatricMemory Dysfunction. Science, 217, 408-417 (1982). The authorshypothesize that a disruption of the central cholinergic system may beresponsible for age-related CNS impairment. (See also, Perry, E. K., TheCholinergic Hypothesis—Ten Years On, Br. Med. Bull., 42, 63-69 (1986)).

[0003] Further evidence for the support of the cholinergic hypothesishas been offered by Sims, et al., Presynaptic Cholineraic Dysfunction inPatients with Dementia, J. Neurochem., 40, 503-509 (1983). These authorshave demonstrated that the acetylcholine neurotransmitter system isimplicated in age-related CNS disorders by showing that activity ofcholinergic markers such as choline acetyltransferase is markedlyreduced in the brains of patients with Alzheimer's disease (AD) incomparison to age-matched controls.

[0004] Additionally, it has been shown that cholinergic neurons whichoriginate at the nucleus basalis of Meynert and project into thehippocampus and cortex show extensive degeneration in Alzheimer'sDisease. See Vogel et al. Cell Loss and Shrinkage in the Nucleus BasalisMeynert Complex in Alzheimer's Disease.

[0005] Neurobiol. Aging, 1, 3-13 (1990); and Whitehouse et al.,Alzheimer's Disease and Senile Dermentia: Loss of Neurons in the BasalForebrain, Science, 215, 1 237-1239 (1982).

[0006] Furthermore, it has been shown that muscarinic antagonists suchas scopolamine can induce cognitive impairments in normal subjectssimilar to that of normal aging. See Sitaram, et al., Human SerialLearning: Enhancement with Arecoline and Choline and Impairment withScopolamine. Science, 201, 274-276 (1978); and Drachman D. A. Memory andCognitive Function in Man: Does the Cholinergic System have a SpecificRole? Neurology, 27, 783-790 (1977). Based on the above research, it iscommonly believed that potentiation of central cholinergic action willbe a useful treatment of conditions exhibiting cognitive decline.

[0007] One strategy to enhance cholinergic neurotransmission has been tomimic the action of acetylcholine at the muscarinic receptors withappropriate agonists. There are three pharmacologically definedreceptors (M₁-M₃) and recently five human receptors (m₁-m₅) have beencloned (Bonner, et al., Identification of a Family of MuscarinicAcetylcholine Receptor Genes, Science, 237, 527-532 (1987); and

[0008] Bonner, T. I., The Molecular Basis of Muscarinic ReceptorDiversity. T.I.N.S., 12, 148-151 (1989). Due to the lack of highlyselective ligands for each subtype, it has not been possible tounambiguously establish the biological role of the individual receptors.However, it is believed that central ml receptors mediate cognition andthe m₂-m₅ subtypes are responsible for side effects (salivation,lacrimation, diarrhea). Immunoprecipitation studies have shown apreponderance of the human ml receptor in the cortex and hippocampus,areas of the brain involved in memory and learning. Ideally, a selectivem₁ agonist would be a desirable agent for treating the cognitive declineassociated with neurodegenerative disorders.

[0009] In addition to age related cognitive decline, muscarinic agentsare also known to be effective in the treatment of psychotic conditions,pain, sleep disorders, depression, seasonal affective disorder andtardive dyskinesias.

[0010] Muscarinic agents are known to influence schizophrenia and otherpsychotic conditions and the atypical antipsychotic clozapine possessesselective m₄ agonist activity which is important for its clinicalprofile (Zorn et al., Clozaoine Is A Potent And Selective Muscarinic M4Receptor Agonist, Eu. J. Pharmacol., 269, R1-R2, (1 994). Clozapine isalso used to treat the tardive dyskinesias that frequently arisefollowing treatment with typical antipsychotics.

[0011] Muscarinic agonists are also known to produce robust analgesia,comparable to that produced by opiate analgesics. (P. Hartvig et al.,Cholineraic mechanisms in pain and analgesia, Trends Pharmacol. Sci., i,75-79, (1989)).

[0012] Muscarinic antagonists are also believed to be effective agentsin treating diseases or syndromes characterized by overactivation ofmuscarinic receptors. Cholinergic regulation of sleep, particularly theREM phase, indicates that the muscarinic agents will be useful intreating sleep disorders such as insomnia and somnolence (D. Reimann etal., Cholinergic Neurotransmission, REM Sleep And Depression, J.Psychosom. Res., 38, 15-25, (1994)). Muscarinic systems also modulatepsychiatric depression (K. Davis et al., Induction of Depression WithOxotremorine In Patients With Alzheimer's Disease, Am. J. Psychiatry,144. 468-471, (1987)), including seasonal affective disorder (S. C.Dilsaver et al., Bright Artificial Light Subsensitizes a CentralMuscarinic Mechanism, Life Sci., 41, 2607-2614, (1987)).

[0013] Muscarinic antagonists are also useful in the treatment ofdiseases associated with altered motility or tone of smooth muscle suchas irritable bowel syndrome, urinary incontinence, diverticular disease,oesophageal achalasia and chronic obstructive airways disease.

[0014] U.S. Pat. No. 4,211,867, issued Jul. 8, 1980, refers to nitrogenheterocyclic carboximidamide derivatives. The compounds are stated topossess hypoglycemic activity.

[0015] U.S. Pat. No. 4,414,211, issued Nov. 8, 1983, refers toheterocyclic derivatives of guanidine. The compounds are stated topossess hypoglycemic activity.

SUMMARY OF THE INVENTION

[0016] The present invention relates to compounds of the formula

[0017] wherein X is NR⁴R⁵, (C₁-C₁₀)alkyl or (C₃-C₁₀)cycloalkyl, whereinsaid (C₃-C₁₀)cycloalkyl may optionally be substituted with from one tothree substituents, preferably one or two substituents, independentlyselected from the group consisting of —OR⁵, (C₁-C₄)alkyl, oxo and aketal of the formula —O—(CH₂)_(n)—O—;

[0018] n is an integer from one to three;

[0019] m is an integer from one to three;

[0020] p is an integer from one to three;

[0021] Y is N or CH;

[0022] Z is NR⁷R⁸, (C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl, pyridyl or phenyl;wherein said phenyl or (C₃-C₁₀)cycloalkyl may optionally be substitutedwith from one to three substituents, preferably one or two substituents,independently selected from the group consisting of (C₁-C₆)alkyl, halo,hydroxy, (C₁-C₆)alkoxy, amino, (C₁-C₆)-alkylamino, di(C₁-C₆)-alkylaminoand trifluoromethoxy;

[0023] R² is phenyl optionally substituted with from one to threesubstituents, preferably one or two substituents, independently selectedfrom the group consisting of (C₁-C₆)alkyl, halo, hydroxy, (C₁-C₆)alkoxy,amino, (C₁-C₆)-alkylamino, di(C₁-C₆)-alkylamino, —CF₃, —CN, —COR⁶,NHCOR⁶ and trifluoromethoxy;

[0024] R³ is phenyl optionally substituted with from one to threesubstituents, preferably one or two substituents, independently selectedfrom the group consisting of (C¹-C₆)alkyl, halo, hydroxy, (C¹-C₆)alkoxy,amino, (C₁-C₆)-alkylamino, di(C₁-C₆)-alkylamino and trifluoromethoxy;

[0025] R⁴ and R⁵ are independently (C₁-C₁₀)alkyl or R⁴ and R⁵ takentogether with the nitrogen atom to which they are attached form a (fiveto nine)-membered saturated heterocyclic ring in which one of the ringatoms may optionally be replaced with a heteroatom selected from thegroup consisting of nitrogen, oxygen and sulfur, wherein said (five tonine)-membered saturated heterocyclic ring may optionally be substitutedwith from one to three substituents, preferably one or two substituents,independently selected from the group consisting of —ORO, (C¹-C₄)alkyl,oxo and a ketal of the formula —O—(CH₂)_(m)—O—; with the proviso thatsaid substituted heterocycles may not be substituted next to aheteroatom by hydroxy or a ketal;

[0026] R⁶ is hydrogen or (C¹-C₆)alkyl; and

[0027] R⁷ and R⁸ are independently (C₁-C₁₀)alkyl or R⁷ and R⁸ takentogether with the nitrogen atom to which they are attached form a (fiveto seven)-membered saturated heterocyclic ring in which one of the ringatoms may optionally be replaced with a heteroatom selected from thegroup consisting of nitrogen, oxygen and sulfur, wherein said (five toseven)-membered saturated heterocyclic ring may optionally besubstituted with from one to three substituents, preferably one or twosubstituents, independently selected from the group consisting of —OR⁶,(C₁-C₄)alkyl, oxo and a ketal of the formula —O—(CH₂)_(p)—O—; with theproviso that said substituted heterocycles may not be substituted in thetwo position by hydroxy or a ketal;

[0028] and the pharmaceutically acceptable salts thereof.

[0029] The present invention also relates to the pharmaceuticallyacceptable acid addition salts of compounds of the formula I. The acidswhich are used to prepare the pharmaceutically acceptable acid additionsalts of the aforementioned base compounds of this invention are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

[0030] The invention also relates to base addition salts of formula I.The chemical bases that may be used as reagents to preparepharmaceutically acceptable base salts of those compounds of formula Ithat are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limitedto, those derived from such pharmacologically acceptable cations such asalkali metal cations (e.g., potassium and sodium) and alkaline earthmetal cations (e.g., calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine-(meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines.

[0031] The above heterocyclic ring systems described as X and Z include,but are not limited to, pyrrolidine, piperidine, thiomorpholine,hexamethyleneimine, heptamethyleneimine, tetrahydrooxazine,tetrahydrothiazine, morpholine, tetrahydrooxazine, thiomorpholine,tetrahydrodiazine, piperazine, oxazolidine, thiazolidine, pyrazolidine,tetrahydrodiazepine, tetrahydrooxazepine, tetrahydrothiazepine,perhydrodiazocine, perhydrodiazonine, perhydroazonine, andperhydrothiazonine.

[0032] The compounds of the invention include all stereoisomers and alloptical isomers of the formula I (e.g., R and S enantiomers) and theirracemic and diastereomeric mixtures. The compounds of the inventioninclude all tautomers and geometric isomers.

[0033] Preferred compounds of the invention are compounds of formula Iwherein:

[0034] Z is pyridyl or phenyl optionally substituted with from one tothree substituents independently selected from the group consisting of(C₁-C₆)alkyl, halo, hydroxy, (C₁-C₆)alkoxy, amino, (C¹-C₆)alkylamino,di(C₁-C₆)-alkylamino and trifluoroalkoxy;

[0035] X is NR⁴R⁵ and R⁴ and R⁵ are taken together with the nitrogenatom to which they are attached to form an optionally substituted fiveto nine membered saturated heterocyclic ring selected from piperidine,pyrrolidine, thiomorpholine, hexamethylenimine, morpholine, thiazolidineand 1,2-tetrahydrooxazine;

[0036] R² is phenyl optionally substituted with halo, hydroxy ormethoxy; and

[0037] R³ is phenyl substituted with one or two substituentsindependently selected from the group consisting of (C₁-C₆)alkyl, halo,hydroxy, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino, di(C¹-C₆)-alkylaminoand trifluoroalkoxy.

[0038] More preferred compounds of the invention are compounds offormula I wherein:

[0039] X is an optionally substituted heterocycle selected frompiperidine and 1,2-tetrahydrooxazine;

[0040] R² is phenyl optionally substituted with halo, hydroxy ormethoxy; and

[0041] R³ is phenyl substituted with one or two substituentsindependently selected from (C₁-C₆)alkyl, halo, hydroxy, (C₁-C₆,)alkoxy,amino, (C₁-C₆)alkylamino di(C₁-C₆)-alkylamino and trifluoroalkoxy.

[0042] More preferred compounds of the invention are those wherein:

[0043] R² is phenyl substituted in the 4-position of the phenyl ringwith fluoro or methoxy; and

[0044] R³ is phenyl substituted with two substituents independentlyselected from (C₁-C₆)alkyl, halo, hydroxy, (C₁-C₆)alkoxy, amino,di(C₁-C₆)-alkylamino and trifluoroalkoxy.

[0045] Most preferred compounds of the invention are those of theformula I wherein X is piperidine substituted in the two position with(C₁-C₄)alkyl and R³ is 2,6-dimethylphenyl.

[0046] Specific examples of preferred compounds of formula I include thefollowing:

[0047]N-[(2,6-dimethyl-phenyl)-(4-fluoro-phenylimino)-methyl]-2-methyl-N′-phenyl-piperidine-1-carboxamidine;

[0048]N-(4-fluoro-phenyl)-2-methyl-N′-[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-benzamidine;

[0049]N-(4-fluoro-phenyl)-2-methyl-N′-([1,2]-oxazinan-2-yl-phenylimino-methyl)-benzamidine;

[0050]N-(4-methoxy-phenyl)-2,6-dimethyl-N′-[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-benzamidine;

[0051]N-(4-fluoro-phenyl)-2-methyl-N′-[(2-methyl-piperidin-1-yl)-o-tollylimino-methyl]-benzamidine;

[0052]N-(4-fluoro-phenyl)-N′-[(4-hydroxy-2-methyl-piperidin-1-yl)-phenylimino-methyl]-2,6-dimethyl-benzamidine;

[0053]N-(4-fluoro-phenyl)-N′-[(4-hydroxy-2-methyl-piperidin-1-yl)-phenylimino-methyl]-2,6-dimethyl-benzamidine;

[0054]N-(4-fluoro-phenyl)-2,6-dimethyl-N′-[(2-methyl-piperidin-1-yl)-(pyridin-3-ylimino)-methyl]-benzamidine;

[0055](3-phenylimino-3-[2-methyl]piperidin-1-yl-1-o-tolyl-propenyl)-(4-fluoro-phenyl)-amine;

[0056](3-phenylimino-3-[1,2]oxazinan-2-yl-1-o-tolyl-propenyl)-(4-fluoro-phenyl)-amine;

[0057](3-phenylimino-3-[1,2]oxazinan-2-yl-1-o-tolyl-propenyl)-(4-methoxy-phenyl)-amine;

[0058]N-[cyclopropylimino-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0059]N-(cyclopropylimino-[1,2]oxazinan-2-yl-methyl)-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0060]N-[cyclopropylimino-(1-methyl-cyclohexyl)-methyl]-N′-(4-fluoro-phenyl)-2-methyl-benzamidine;and

[0061](3-cyciopropylimino-3-[1,2]oxazinan-2-yl-1-o-tolyl-propenyl)-(4-fluoro-phenyl)-amine.

[0062] Other compounds of the invention include:

[0063] N-phenyl-N′-( phenylimino-pyrrolidin-1-yl-methyl)-benzamidine;

[0064] N-phenyl-N′-(phenylimino-piperidin-1-yl-methyl)-benzamidine;

[0065] N-phenyl-N′-(phenylimino-thiomorpholin-4-yl-methyl)-benzamidine;

[0066]N,N-diethyl-N′-phenyl-N″-(phenyl-phenylamino-methylene)-guanidine;

[0067]N-(4-fluoro-phenyl)-N′-(phenylimino-pyrrolidin-1-yl-methyl)-benzamidine;

[0068]N-(4-methoxy-phenyl)-N′-(phenylimino-pyrrolidin-1-yl-methyl)-benzamidine;

[0069]N-(4-chloro-phenyl)-N′-(phenylimino-pyrrolidin-1-yl-methyl)-benzamidine;

[0070] N-(azepan-1-yl-phenylimino-methyl)-N′-phenyl-benzamidine;

[0071]N-(azepan-1-yl-phenylimino-methyl)-N′-(4-methoxy-phenyl)-benzamidine;

[0072]N-(azepan-1-yl-phenylimino-methyl)-N′-(4-fluoro-phenyl)-benzamidine;

[0073]2-methyl-N-phenyl-N′-(phenylimino-pyrrolidin-1-yl-methyl)-benzamidine;

[0074]N-[(4-methyl-piperidin-1-y)-phenylimino-methyl-N′-phenyl-benzamidine;

[0075] N-(azocan-1-yl-phenylimino-methyl)-N′-phenyl-benzamidine;

[0076]N-[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-N′-phenyl-benzamidine;

[0077]N-[(3-methyl-piperidin-1-yl)-phenylimino-methyl]-N′-phenyl-benzamidine;

[0078]N-[(4-hydroxy-piperidin-1-yl)-phenylimino-methyl]-2-methyl-N′-phenyl-benzamidine;

[0079]N-1(4-fluoro-phenylimino)-pyrrolidin-1-yl-methyl]-N′-phenyl-benzamidine;

[0080]N-(4-fluoro-phenyl)-N′-[(4-hydroxy-piperidin-1-yl)-phenylimino-methyl]-2-methyl-benzamidine;

[0081]N-[(2-fluoro-phenylimino)-pyrrolidin-1-yl-methyl]-N′-phenyl-benzamidine;

[0082]N-[(4-fluoro-phenylimino)-(4-hydroxy-piperidin-1-yl)-methyl]-2-methyl-N′-phenyl-benzamidine;

[0083]2-chloro-N-phenyl-N′-(phenylimino-pyrrolidin-1-yl-methyl)-benzamidine;

[0084]N-[(2,6-dimethyl-phenyl)-phenylimino-methyl]-N′-phenyl-pyrrolidine-1-carboxamidine;

[0085]N-[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-N′-phenyl-benzamidine;

[0086]N-[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-N′-phenyl-benzamidine;

[0087]N-(azepan-1-yl-phenylimino-methyl)-N′-(4-fluoro-phenyl)-2-methyl-benzamidine;

[0088]N-(4-fluoro-phenyl)-N′-[(2-fluoro-phenylimino)-(4-hydroxy-piperidin-1-yl)-methyl]-2-methyl-benzamidine;

[0089]N-[(2-chloro-phenyl)-(4-fluoro-phenylimino)-methyl]-2-methyl-N′-phenyl-piperidine-1-carboxamidine;

[0090]N-[(3-hydroxy-piperidin-1-yl)-phenylimino-methyl]-N′-phenyl-benzamidine;

[0091]N-[(2-fluoro-phenyl)-phenylimino-methyl]-N′-phenyl-pyrrolidine-1-carboxamidine;

[0092]N-(4-fluoro-phenyl)-2-methyl-N′-[(2-methyl-piperidin-1-yl)-(pyridin-4-ylimino)-methyl]-benzamidine;

[0093] N-([1,2]oxazinan-2-yl-phenylimino-methyl)-N′-phenyl-benzamidine;

[0094]N-[(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylimino-methyl]-N′-phenyl-benzamidine;

[0095]N-(4-fluoro-phenyl)-2-methyl-N′-[(1-methyl-cyclohexyl)-phenylimino-methyl]-benzamidine;

[0096]N-(4-fluoro-phenyl)-N′-[(4-fluoro-phenylimino)-(2-methyl-piperidin-1-yl)-methyl]-2,6-dimethyl-benzamidine;

[0097]2,6-difluoro-N-(4-fluoro-phenyl)-N′-[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-benzamidine;

[0098]2,6-dichloro-N-(4-fluoro-phenyl)-N′-[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-benzamidine;

[0099]N-[(4-chloro-phenylimino)-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0100]N-(adamantan-1-yl-phenylimino-methyl)-N′-(4-fluoro-phenyl)-2-methyl-benzamidine;

[0101]N-[(2,6-dimethyl-piperidin-1-yl)-phenylimino-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0102]N-[azepan-1-yl-(4-fluoro-phenylimino)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0103] N-(4-fluoro-phenyl)-N′-[(4-fluoro-phenylimino)-[1,2]oxazinan-2-yl-methyl]-2,6-dimethyl-benzamidine;

[0104]2,6difluoro-N-(4-fluoro-phenyl)-N′-[(4-fluoro-phenylimino)-(2-methyl-piperidin-1-yl)-methyl]-benzamidine;

[0105]N-[(2,6-dimethyl-piperidin-1-yl)-(4-fluoro-phenylimino)-methyl]-2,6-difluoro-N′-(4-fluoro-phenyl)-benzamidine;

[0106]N-(azepan-1-yl-phenylimino-methyl)-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0107]N-[(2,6-dimethyl-piperidin-1-yl)-(4-fluoro-phenylimino)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0108]N-[(2,6-dimethyl-piperidin-1-yl)-phenylimino-methyl]-2,6-difluoro-N′-(4-fluoro-phenyl)-benzamidine;

[0109]N-(azepan-1-yl-phenylimino-methyl)-2,6-difluoro-N′-(4-fluoro-phenyl)-benzamidine;

[0110]N-[azepan-1-yl-(4-fluoro-phenylimino)-methyl]-2,6-difluoro-N′-(4-fluoro-phenyl)-benzamidine;

[0111]N-[(2-ethyl-piperidin-1-yl)-phenylimino-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0112]N-[(2,6-dimethyl-piperidin-1-yl)-phenylimino-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0113]N-(4-methoxy-phenyl)-2-methyl-N′[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-benzamidine;

[0114] N-(4-fluoro-phenyl)-2, 6-dimethyl-N′-([1,2]oxazinan-2-yl-phenylimino-methyl)-benzamidine;

[0115]N-(4-fluoro-phenyl)-N′-1(3-hydroxy-piperidin-1-yl)-phenylimino-methyl-2,6-dimethyl-benzamidine;

[0116]N-(4-fluoro-phenyl)-2,6-dimethyl-N′-[(4-oxo-piperidin-1-yl)-phenylimino-methyl]-benzamidine;

[0117]N-[(4-amino-phenylimino)-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0118]N-(4-fluoro-phenyl)-2,6-dimethyl-N′-[(2-methyl-4-oxo-piperidin-1-yl)-phenylimino-methyl]-benzamidine;

[0119]N-(4-fluoro-phenyl)-N′-[(3-hydroxy-piperidin-1-yl)-phenylimino-methyl]-2-methyl-benzamidine;

[0120]N-(4-methoxy-phenyl)-2,6-dimethyl-N′-([1,2]oxazinan-2-yl-phenylimino-methyl)-benzamidine;

[0121]N-(4-hydroxy-phenyl)-2,6-dimethyl-N′-[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-benzamidine;

[0122]N-(azepan-1-yl-phenylimino-methyl)-N′-(4-methoxy-phenyl)-2,6-dimethyl-benzamidine;

[0123]N-(4-fluoro-phenyl)-2-methyl-N′-[(4-oxo-piperidin-1-yl)-phenylimino-methyl]-benzamidine;

[0124]N-(4-fluoro-phenyl)-2-methyl-N′-[(2-methyl-4-oxo-piperidin-1-yl)-phenylimino-methyl]-benzamidine;

[0125]N-[(3-amino-phenylimino)-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0126]N-(4-fluoro-phenyl)-N′-[(4-hydroxy-piperidin-1-yl)-phenylimino-methyl]-2,6-dimethyl-benzamidine;

[0127]N-(4-fluoro-phenyl)-N′-[(4-hydroxy-2-methyl-piperidin-1-yl)-phenylimino-methyl]-2,6-dimethyl-benzamidine;

[0128]N-[(3-amino-phenylimino)-(2-methyl-piperidin-1-yl)-methyl]-2,6-dimethyl-N′-(4-trifluoromethoxy-phenyl)-benzamidine;

[0129]2,6-dimethyl-N-[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-N′-(4-trifluoromethoxy-phenyl)-benzamidine;

[0130]N-(4-fluoro-phenyl)-2,6-dimethyl-N′-(morpholin-4-yl-phenylimino-methyl)-benzamidine;

[0131]N-(4-fluoro-phenyl)-2,6-dimethyl-N′-[(2-methyl-piperidin-1-yl)-m-tolylimino-methyl]-benzamidine;

[0132]N-(4-fluoro-phenyl)-N′-[(3-fluoro-phenylimino)-(2-methyl-piperidin-1-yl)-methyl]-2,6-dimethyl-benzamidine;

[0133]N-[(2-chloro-phenylimino)-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2-methyl-benzamidine;

[0134]N-(4-fluoro-phenyl)-N′-[(2-methoxy-phenylimino)-(2-methyl-piperidin-1-yl)-methyl]-2-methyl-benzamidine;

[0135]N-(4-fluoro-phenyl)-N′-[(3-methoxy-phenylimino)-(2-methyl-piperidin-1-yl)-methyl]-2,6-dimethyl-benzamidine;

[0136]N-(4-fluoro-phenyl)-2,6-dimethyl-N′-[(2-methyl-piperidin-1-yl)-o-tolylimino-methyl]-benzamidine;

[0137]N-[(2-chloro-phenylimino)-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0138] (3-phenylimino-3-pyrrolidin-1-yl-1-phenyl-propenyl)-phenylamine;

[0139] (3-phenylimino-3-thiazolidin-3-yl-1-phenyl-propenyl)-phenylamine;

[0140](3-phenylimino-3-[2-methyl]piperidin-1-yl-1-[2-chlorophenyl]-propenyl)-(4-fluorophenyl)-amine;

[0141](3-[4-fluorophenylimino]-3-[2-methyl]piperidin-1-yl-1-o-tolyl-propenyl)-(4-fluoro-phenyl)-amine;

[0142](3-phenylimino-3-[2-methyl]piperidin-1-yl-1-phenyl-propenyl)-phenylamine;

[0143](3-cyclohexylimino-3-[1,2]oxazinan-2-yl-1-o-tolyl-propenyl)-(4-fluoro-phenyl)-amine;

[0144]N-[cyclohexylimino-(1-methyl-cyclohexyl)-methyl]-N′-(4-fluoro-phenyl)-2-methyl-benzamidine;

[0145]N-[cyclohexylimino-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0146]N-[cyclohexylimino-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2-methyl-benzamidine;

[0147]N-[sec-butylimino-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0148]N-(4-fluoro-phenyl)-N′-[isopropylimino-(2-methyl-piperidin-1-yl)-methyl]-2,6-dimethyl-benzamidine;

[0149][3-cyclohexylimino-3-(2-methyl-piperidin-1-yl)-1-o-tolyl-propenyl]-(4-fluoro-phenyl)-amine;

[0150]N-(adamantan-1-yl-cyclohexylimino-methyl)-N′-(4-fluoro-phenyl)-2-methyl-benzamidine;

[0151]N-[cyclobutylimino-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0152]N-[cyclopropylimino-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2-methyl-benzamidine;

[0153]N-[cyclopropylimino-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-methoxy-phenyl)-2,6-dimethyl-benzamidine;

[0154]N-[cyclopropylmethylimino-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0155] (3-cyclopropylimino-3-[1,2]oxazinan-2-yl-1-phenyl-propenyl)-(4-fluoro-phenyl)-amine;

[0156]N-[allylimino-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6-dimethyl-benzamidine;

[0157]N-(4-fluoro-phenyl)-2,6-dimethyl-N′-[(2-methyl-piperidin-1-yl)-(morpholin-4-ylimino)-methyl]-benzamidine;

[0158]N-(4-fluoro-phenyl)-2,6-dimethyl-N′-[(2-methyl-piperidin-1-yl)-(piperidin-1-ylimino)-methyl]-benzamidine;and

[0159]N-(4-fluoro-phenyl)-2,6-dimethyl-N′-[(2-methyl-cyclopropylimino)-(2-methyl-piperidin-1-yl)-methyl]-benzamidine.

[0160] The present invention also relates to a pharmaceuticalcomposition for treating or preventing a disease or condition, thetreatment or prevention of which can be effected or facilitated byenhancing cholinergic neurotransmission in a mammal, comprising amuscarinic receptor binding effective amount of a compound of formula Ior a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

[0161] The present invention also relates to a method of treating orpreventing a disease or condition, the treatment or prevention of whichcan be effected or facilitated by enhancing cholinergicneurotransmission in a mammal, comprising administering to said mammal amuscarinic receptor binding effective amount of a compound of formula Ior a pharmaceutically acceptable salt thereof.

[0162] The present invention also relates to a pharmaceuticalcomposition for treating or preventing a disease or condition, thetreatment or prevention of which can be effected or facilitated byenhancing cholinergic neurotransmission in a mammal, comprisingadministering to said mammal an amount of a compound of formula I or apharmaceutically acceptable salt thereof that is effective in treatingor preventing such condition.

[0163] The present invention also relates to a method of treating orpreventing a disease or condition, the treatment or prevention of whichcan be effected or facilitated by enhancing cholinergicneurotransmission in a mammal, comprising administering to said mammalan amount of a compound of formula I or a pharmaceutically acceptablesalt thereof that is effective in treating or preventing such condition.

[0164] The present invention also relates to a method of treating,preventing or diagnosing a disease or condition selected from the groupconsisting of psychotic disorders, pain, sleep disorders, depression,Alzheimer's disease, tardive dyskinesia, Picks disease, Huntington'schorea, Friederich's ataxia, Gilles de la Tourette's disease, Down'sSyndrome, attention-deficit disorder, multi-infarct dementia, andage-related cognitive decline (ARCD) in a mammal, comprisingadministering to a mammal, including a human, in need of such treatment,prevention or diagnosis an amount of a compound according to claim 1effective in treating, preventing or diagnosing such condition.

[0165] The present invention also relates to a pharmaceuticalcomposition for treating, preventing or diagnosing a disease orcondition selected from the group consisting of psychotic disorders,pain, sleep disorders, depression, Alzheimer's disease, tardivedyskinesia, Picks disease, Huntington's chorea, Friederich's ataxia,Gilles de la Tourette's disease, Down's syndrome, attention-deficitdisorder, multi- infarct dementia, and age-related cognitive decline(ARCD) in a mammal, including a human, comprising an amount of acompound according to claim 1 effective in treating, preventing ordiagnosing such condition and a pharmaceutically acceptable carrier.

[0166] Unless otherwise indicated, the alkyl and alkenyl groups referredto herein, as well as the alkyl moieties of other groups referred toherein (e.g., alkoxy), may be linear or branched, and they may also becyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or belinear or branched and contain cyclic moieties. Unless otherwiseindicated, halogen includes fluorine, chlorine, bromine, and iodine.

[0167] The compounds of formula I contain olefin or imine bonds andtherefore may exist in cis or trans forms. This invention relates to allisomers and all stereoisomers of compounds of the formula I, andmixtures thereof.

[0168] The phrase “a ketal of the formula —O—(CH₂),—O—” when used hereinrefers to a spiro group that can be added to a ketone in the presence ofan acid catalyst and a glycol.

[0169] “Enhancing cholinergic neurotransmission,” when used herein,refers to improving the neuronal process whereby acetylcholine isreleased by a presynaptic cell upon excitation and crosses the synapseto stimulate or inhibit the post-synaptic cell. The compounds of theinvention also function by increasing the cholinergic response bymimicking the action of acetylcholine at the cholinergic receptors.

[0170] When X is NR⁴R⁵ and R⁴ and R⁶ together form an optionallysubstituted (three to nine)-membered heterocyclic ring and when Z isNR⁷R⁸ and R⁷ and R⁸ together form an optionally substituted (five toseven)-membered saturated heterocyclic ring then one of skill in the artwill appreciate that the following rings are meant to be included withinthese definitions. 5 MEMBERED HETEROCYCLES

Name A B D E Reference pyrrolidine C C C C US 3,095,423; US 3,109,005.isoxazolidine O C C C DE 2,339,185; Synthesis, 5, 426-428 (1982); US2,762,815; Arzneim. Forsch., 27, 766-770 (1977). 1,3 oxazolidin-3- C O CC Parravicini et al., Farmaco Ed.Sci., 31, yl 49-57 (1976); Kricheldorf,Makromol. Chem., 176, 57-74 (1975). isothiazolidine S C C C EP 626,377.1,3 thiazolidin-3- C S C C Lance et al., Bull. Soc. Chim. Fr., yl2053-2056 (1971); Barbry et al., J. Chem. Soc. Perkin Trans. 2, 1, 133-140 (1990); Hansen et al., Tetrahedron Lett., 35, 38, 6971-6974 (1994).1,2 pyrazolidin-2- N C C C Stetter et al.,Chem. Ber., 98, 3228- yl 3235(1965); Kornett, J.Pharm. Sci., 58, 724-727 (1969); Oppolzer,Tetrahedron Lett., 35, 3091-3094 (1970). 1,3 pyrazolidin-1- C N C CFreter et al., Justus Liebigs Ann. yl Chem., 607, 174-184 (1957).

[0171] 6 MEMBERED HETEROCYCLES

Name F G I K L Reference piperidine C C C C C US 5,364,943 1,2tetrahydro O C C C C Khomutov et al., Bull. Acad. Sci. oxazin-2-yl USSRDiv. Chem. Sci., 1006-1008 (1962). 1,3 tetrahydro C O C C C Kalyuskii etal., J. Org. Chem., 25, oxazin-3-yl 10, 1989-1991 (1989); Linde et al.,Arzneim. Forsch., 28, 937-939 (1978). morpholine C C O C C J.A.C.S., 47,2966 (1925); J.A.C.S., 58, 2338 (1936). 1,2 tetrahydro S C C C CKharasch, J. Org. Chem., 28, 1901- thiazin-2-yl 1902 (1963). 1,3tetrahydro C S C C C Bergmann et al., Recl. Trav. Chim. thiazin-3-ylPays-Bas., 78, 327-330 (1959). thiomorpholino C C S C C Davies, J. Chem.Soc., 117, 298- 306 (1920). 1,2 tetrahydro N C C C C Baranger et al.,Bull. Soc. Chim. Fr., diazin-2-yl 704, 708 (1957); Selenin et al., Khim.Geterotsikl. Soedin., 530, 533 (1968); Testa, Farmaco Ed. Sci., 26,950-954 (1971). 1,3 tetrahydro C N C C C Skaric et al., Croat. Chem.Acta., diazin-1-yl 38, 1-4 (1966). piperazine C C N C C J.A.C.S., 51,3074 (1929); US 3,037,023.

[0172] 7 MEMBERED MONOCYCLIC HETEROCYCLES

Name L M N O P Q Reference 1,2 perhydro O C C C C C Amiaiky et al.,Synthesis, 5, 426- oxazepin-2-yl 428, (1982). 1,3 perhydro C O C C C CBergmann et al., Recl. Trav. Chim. oxazepin-3-yl Pays-Bas., 78, 327-330(1959). 1,4 perhydro C C O C C C Farberow et al., Zh. Obshch.oxazepin-4-yl Khim., 25, 133-135 (1955). 1,2 perhydro C S C C C C Grobet al., Helv. Chim. Acta., 57, thiazepin-2-yl 2562-2571 (1974). 1,2perhydro C C S C C C Black, J. Chem. Soc. C, 1708- thiazepin-2-yl 1710(1966); Can. J. Chem., 49, 2612-2616 (1971); J. Org. Chem., 46, 7,1239-1243 (1981); and J. Org. Chem., 25, 1953- 1956 (1960); DE1,195,317. 1,2 perhydro N C C C C C Rutjes et al., Tetrahedron Lett.,diazepin-1-yl 32, 45, 6629-6632 (1991); and Fritschi et al., Helv. Chem.Acta., 74, 8, 2024-2034 (1991). 1,3 perhydro C N C C C C Gunawardane,Indian J. Chem. diazepin-1-yl Sect. A, 27, 5, 380-386 (1988). 1,4perhydro C C N C C C Poppelsdorf et al., J. Org. Chem., diazepin-1-yl26, 131-134 (1961); Ziegler et al., J. Med. Chem., 33, 1, 142-146(1990); and Dickerman et al., J. Org. Chem., 14, 530-536 (1949).hexamethyl C C C C C C Benson et al., J. Amer. Chem. eneimin-1-yl Soc.,70, 2115-2117 (1948); Wang et al., J. Amer. Chem. Soc., 114, 1, 248-255(1992); U.S. 1,253,558; and U.S. 1,253,456.

[0173] 8 MEMBERED HETEROCYCLES

Name X₁ X₂ X₃ X₄ X₅ X₆ X₇ X₈ Reference heptamethy C C C C C C C CGuttieri et al., J. leneimine Org. Chem., 49, 16, 2875-2880 (1984). 1,2N C C C C C C C J. Org. Chem., perhydro 37, 1851 diazocine (1972); andJ.A.C.S., 92, 4922-4925 (1970). 1,4 C C N C C C C C Majchrzak et al.,perhydro Acta Pol. diazocine Pharm., 32, 145 (1975). 1,5 C C C N C C C CAlder et al., J. perhydro Chem. Soc. diazocine Perkin Trans. 2, 3,411-418 (1984).

[0174] 9 MEMBERED HETEROCYCLES

Name Y¹ Y² Y³ Y⁴ Y⁵ Y⁶ Y⁷ Y⁸ Reference octahydroazonine C C C C C C C CBlicke, J. Amer. Chem. Soc., 76, 2317-2319 (1954); and U.S. 2,051,575.1,5 C C C S C C C C Wise et al., J. perhydrothiazonine Med. Chem., 17,11, 1232-1234 (1974). 1,4 perhydro C C N C C C C C Alder et al.,diazonine Tetrahedron Lett., 23, 40, 4181-4184 (1982). 1,5 perhydro C CC N C C C C Croker et al., diazonine Tetrahedron Lett., 24, 14,1559-1560 (1983).

DETAILED DESCRIPTION OF THE INVENTION

[0175] The compounds of formula I can be prepared according to themethods of Schemes 1-5. In the reaction Schemes and discussion thatfollow, A, m, n, p, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X, Y and Z, unlessotherwise indicated, are as defined above for formula I.

[0176] Scheme 1 refers to the preparation of compounds of the formula I,wherein Y is nitrogen, and X is NR⁴R⁵ from compounds of the formula III.Compounds of the formula III are commercially available or can be madebe methods available to one of ordinary skill in the art.

[0177] A compound of the formula III is converted into a compound of theformula II by sequentially reacting the compound of the formula III witha compound of the formula X—H and a base in a reaction inert solventfollowed by reaction with ammonia. Suitable reaction inert solventsinclude ethers such as diethyl ether, tetrahydrofuran and diisopropylether, acetone or acetonitrile, preferably diethyl ether. Suitable basesinclude triethylamine, pyridine, diisopropylethylamine, preferablytriethylamine. Ammonia can be added in the form of a gas or as asolution in an organic solvent. Suitable organic solvents includealcohols such as ethanol and isopropanol, or benzene or toluene. Whenammonia is added as a solution the preferred solvent is isopropanol. Thetemperature of the reaction during the addition of the reactant X—H maybe in the range from about −78° C. to about 25° C., preferably 0° C. toabout 25° C. The temperature for the reaction with ammonia is in therange from about 0° C. to about 40° C., preferably about 25° C.

[0178] The compound of formula II is converted into a compound offormula I by reaction of the compound of formula II with a strong basein a reaction inert solvent, followed by addition of a compound of theformula

[0179] Compounds of the formula IV can be prepared according to themethod described in J. Heterocyclic Chem., 18, 659 (1981). Suitablebases include sodium hydride, potassium hydride and n-butyl lithium,preferably sodium hydride. Suitable solvents include ethers such astetrahydrofuran, and diethyl ether, dimethylformamide, preferablytetrahydrofuran. The temperature during the addition of the strong basemay be in the range from about 0° C. to about 35° C., preferably about25° C. The temperature during the addition of the compound of formula IVmay be in the range from about −25° C. to about 25° C., preferably 0° C.to about 25° C.

[0180] Scheme 2 refers to an alternate preparation of compounds of theformula I, wherein Y is nitrogen and X is NR⁴R^(5,) from compounds ofthe formula III.

[0181] A compound of the formula III is converted into a compound of theformula V by sequentially reacting the compound of the formula III witha compound of the formula X—H and a base in a reaction inert solventfollowed by reaction with a compound of the formula

[0182] Suitable reaction inert solvents include ethers such as diethylether, tetrahydrofuran and diisopropyl ether, acetone or acetonitrile,preferably diethyl ether. Suitable bases include triethylamine,pyridine, diisopropylethylamine, preferably triethylamine. The compoundof formula VI is preferably dissolved in a small amount of the reactioninert solvent and is then added dropwise to the reaction, after thereaction with the compound of the formula X—H is complete. Compounds ofthe formula VI can be made according to the methods described in Eur. J.Med. Chem. Chim. Ther., 12, 365 (1977) and Australian J. Chem., 30, 2225(1977). The temperature of the reaction during the addition of thereactant X—H may be in the range from about −78° C. to about 25° C.,preferably O° C. to about 25° C. The temperature for the reaction withthe compound of formula VI is in the range from about −10° C. to about80° C., preferably about 0° C. to about 40° C. (i.e. the boiling pointof the preferred solvent).

[0183] The compound of the formula V is converted into a compound offormula I by reaction with a compound of the formula R²NH₂ in a reactioninert solvent at a temperature from about 25° C. to about 100° C.,preferably at about 100° C. Suitable solvents include (1,4)-dioxane,tetrahydrofuran, dimethylformamide, acetonitrile or t-butanol,preferably (1,4)-dioxane or t-butanol.

[0184] Scheme 3 refers to the preparation of compounds of the formula I,wherein Y is nitrogen and X is NR⁴R⁵, from compounds of the formula IV.Compounds of the formula IV can be made according to the methodsdescribed in J. Heterocyclic Chem., 18, 659 (1981).

[0185] Compounds of the formula IV are converted into compounds of theformula VIII by sequentially reacting the compound of formula IV in areaction inert solvent with a thiocyanate followed by reaction with acompound of the formula Z—NH₂. Suitable thiocyanates include sodiumthiocyanate or potassium thiocyanate, preferably sodium thiocyanate.Suitable solvents include acetone, ethers (such as tetrahydrofuran) andacetonitrile, preferably acetone. The temperature for the reaction withthe thiocyanate is in the range from about −35° C. to about 10° C.,preferably 0° C. The temperature of the reaction with the compound ofthe formula Z—NH₂ is in the range from about −35° C. to about 35° C.,preferably about 25° C. Variations of the aforesaid reaction can befound in Goerdeler, et al., Chem. Ber., 101, 3475 (1968).

[0186] The compound of formula VII can be converted into a compound offormula VII by reaction with a methylating agent in a reaction inertsolvent. Suitable methylating agents include methyl iodide,trimethyloxonium tetrafluoroborate or methyl trifluoromethanesulfonate,preferably methyl iodide or trimethyloxonium tetrafluoroborate. Suitablereaction inert solvents include methylene chloride, 1,2 dichloroethaneor acetone, preferably acetone or methylene chloride. The temperaturefor the aforesaid process may be in the range from about 0° C. to about90° C., preferably 25° C. to about 60° C.

[0187] The compound of formula VII can be converted to a compound offormula I by reaction with a compound of the formula X—H in a reactioninert solvent. Suitable reaction inert solvents include (1,4)-dioxane,acetonitrile, t-butanol or dimethylformamide, preferably (1,4)-dioxane.The temperature of the aforesaid reaction is in the range from about 25°C. to about 180° C., preferably 100° C. (i.e. the boiling point of thepreferred solvent).

[0188] Alternatively, a compound of the formula VII can be converted toa compound of the formula I by reaction with a compound of the formulaX—H in the presence of silver nitrate and a base in a reaction inertsolvent, in the dark. Suitable bases include triethylamine, pyridine,diisopropylethylamine, preferably triethylamine.

[0189] Suitable reaction inert solvents include acetonitrile, methylenechloride or 1,2-dichloroethane, preferably acetonitrile. The temperatureof the aforesaid reaction is in the range from about −15° C. to about60° C., preferably about 0° C. to about 25° C. Variations of theaforesaid reaction can be found in Bosin et al., J. Org. Chem., 38,1591(1973).

[0190] Alternatively, a compound of formula I can be prepared directlyfrom a compound of the formula VIII by reaction with a compound of theformula X—H and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCl) in a reaction inert solvent. Suitable reactioninert solvents include dimethylformamide, tetrahydrofuran, diethyl etheror methylene chloride, preferably dimethylformamide or tetrahydrofuran.The temperature of the aforesaid reaction is in the range from about 0°C. to about 35° C., preferably about 25° C. Variations of the aforesaidreaction can be found in Atwal et al., Tetrahedron Letters, 30, 7313,(1989).

[0191] Scheme 4 refers to the preparation of compounds of the formula I,wherein Y is —CH— and X is NR⁴R⁵, from compounds of the formula XII.Compounds of the formula XII are commercially available or can be madeby methods well known to those of ordinary skill in the art.

[0192] Referring to Scheme 4, a compound of the formula XII is convertedinto a compound of the formula XI by reaction with an isothiocyanate ofthe formula Z—N═C═S in the presence of a strong base in a reaction inertsolvent. Suitable bases include lithium-, sodium- orpotassium-bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, or sodium hydride, preferably lithium bis(trimethylsilyl)amide.Suitable reaction inert solvents include tetrahydrofuran, diethylether,methylene chloride or toluene, preferably tetrahydrofuran. Thetemperature of the aforesaid reaction is in the range from about −78° C.to about 80° C., preferably −78° C. to about 250° C.

[0193] The compound of formula XI is converted into a compound of theformula X by reaction with a compound of the formula R²—NH₂ and acatalytic amount (5-20%) of acid in a reaction inert solvent. Suitableacid catalysts are the hydrochloride salt of the reactant R²—NH₂ (e.g.,R²—NH₂.HCl), toluenesulfonic acid or camphorsulphonic acid, preferablyR²—NH₂.HCl. Suitable reaction inert solvents include benzene, toluene orxylene, preferably benzene. The temperature of the aforesaid reaction isin the range of about 50° C. to about 150° C., preferably about 80° C.,i.e. the boiling point of the preferred solvent. The reaction isfacilitated by removal of water. Suitable dehydrating agents includeazeotropic removal of water (via a Dean-Stark trap) or molecular sieves,preferably azeotropic removal of water.

[0194] The compound of formula X can be converted into a compound offormula IX by reaction with a methylating agent in a reaction inertsolvent. Suitable methylating agents include methyl iodide,trimethyloxonium tetrafluoroborate or methyl trifluoromethanesulfonate,preferably trimethyloxonium tetrafluoroborate. Suitable reaction inertsolvents include methylene chloride, 1,2-dichloroethane or acetone,preferably methylene chloride. The temperature for the aforesaid processmay be in the range from about −10° C. to about 30° C., preferably about0° C. to about 25° C.

[0195] The compound of formula IX is converted into a compound offormula I by reaction with a compound of the formula X—H in a reactioninert solvent. Suitable reaction inert solvents include 1,4-dioxane,acetonitrile, t-butanol or dimethylformamide, preferably (1,4)-dioxane.The temperature of the aforesaid reaction is in the range from about 25°C. to about 180° C., preferably 100° C. (i.e. the boiling point of thepreferred solvent).

[0196] Alternatively, a compound of the formula IX can be converted to acompound of formula I by reaction with a compound of the formula X—H inthe presence of silver nitrate and a base in a reaction inert solvent,in the dark. Suitable bases include triethylamine, pyridine, ordiisopropylethylamine, preferably triethylamine. Suitable reaction inertsolvents include acetonitrile, methylene chloride or 1,2-dichloroethane,preferably acetonitrile. The temperature of the aforesaid reaction is inthe range from about −15° C. to about 600° C., preferably about 0° C. toabout 25° C.

[0197] Scheme 5 refers to the preparation of compounds of the formula Ifrom compounds of the formula IV. Compounds of the formula IV can beprepared according to the methods described in J. Heterocyclic Chem.,18, 659 (1981).

[0198] Referring to Scheme 5, a compound of the formula IV is convertedinto a compound of formula XIV by reaction with ammonia in a reactioninert solvent. Suitable reaction inert solvents include alcohols such asethanol, isopropanol, or butanol, benzene or toluene, preferablytoluene. Ammonia can be added in the form of a gas or as a solution inan organic solvent. When ammonia is added as a solution the preferredsolvent is the solvent that has been used as the reaction inert solvent(e.g., toluene). The temperature for the reaction is in the range fromabout 10° C. to about 40° C., preferably about 25° C.

[0199] The compound of formula XIV is converted into a compound of theformula XIII by reaction with a compound of the formula X—C(═O)—Cl, inthe presence of a base and a catalytic amount (5-20%) of4-dimethylaminopyridine, in a reaction inert solvent. Suitable basesinclude triethylamine or diisopropylethylamine, preferablytriethylamine. Suitable reaction inert solvents include methylenechloride, 1,2-dichloroethane or tetrahydrofuran, preferably methylenechloride. The temperature of the aforesaid reaction is in the range fromabout 0° C. to about 50° C., preferably about 25° C. Compounds of theformula X—C(═O)—Cl are commercially available or can be made by themethods of Rost et al. J. Am. Pharm. Assoc., 46, 290 (1957) as well asother methods well known to those of ordinary skill in the art.

[0200] Compounds of the formula XIII can be converted into compounds ofthe formula I by sequentially reacting the compound of formula XIII witha chlorinating agent followed by reaction with a compound of the formulaZ—NH₂ in a reaction inert solvent. Suitable chlorinating agents includephosphorous oxychloride or phosphorous pentachloride, preferablyphosphorous pentachloride. Suitable reaction inert solvents includetetrahydrofuran, methylene chloride or 1,2-dichloroethane, preferablytetrahydrofuran. The temperature of the chlorination step of theaforesaid reaction is from about 100° C. to about 150° C., preferablyabout 125° C. The temperature of the reaction with a compound of theformula Z—NH₂ is from about 0° C. to about 50° C., preferably about 25°C.

[0201] Alternatively, a compound of the formula I can be prepareddirectly from a compound of the formula XIV by reaction with a compoundof the formula

[0202] in a reaction inert solvent. Compounds of the formula XV can beprepared according to the method described in J. Heterocyclic Chem., 18,659 (1 981). Suitable reaction inert solvents include diethyl ether,tetrahydrofuran, methylene chloride, 1,2-dichloroethane, preferablytetrahydrofuran. The temperature of the aforesaid reaction is in therange from about −20° C. to about 80° C., preferably about 25° C.

[0203] Compounds of the formula I which contain a hydroxy moiety on theX or Z (i.e. Z is not phenyl) or both rings can be prepared fromcompounds of the formula I in which the X and/or Z moiety contains aketal. The ketal moiety can be introduced on any of the startingmaterials described in Schemes 1-5 which can support a ketone group onany or both of the X or Z rings. One of ordinary skill in the art wouldbe able to convert the ketal to an alcohol by standard methods.

[0204] Compounds of formula I containing a hydroxy group on either orboth R² or R³ rings can be prepared from compounds of formula Icontaining a methoxy group on either or both R² or R³ rings according tomethods well known to those of ordinary skill in the art.

[0205] The compounds of the formula I which are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate a compound of the formula Ifrom the reaction mixture as a pharmaceutically unacceptable salt andthen simply convert the latter back to the free base compound bytreatment with an alkaline reagent, and subsequently convert the freebase to a pharmaceutically acceptable acid addition salt. The acidaddition salts of the base compounds of this invention are readilyprepared by treating the base compound with a substantially equivalentamount of the chosen mineral or organic acid in an aqueous solventmedium or in a suitable organic solvent such as methanol or ethanol.Upon careful evaporation of the solvent, the desired solid salt isobtained.

[0206] The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the base compounds of this inventionare those which form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [ie.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0207] Those compounds of the formula I which are acidic in nature arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal andalkaline-earth metal salts and particular, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the herein described acidic compounds offormula I. These non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium, calcium, andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction of maximum product of yields of the desired final product.

[0208] The compounds of this invention will be useful for the treatmentof Alzheimer's Disease (AD) or senile dementia of the Alzheimer's type(SDAT). In AD, it has been found that the density of the M₂ receptors isdecreased while the density of the post-synaptic M₁ receptors remainsunaltered. A selective m₁(M₁) muscarinic agonist would thus beefficacious at early and advanced stages of AD, and would displayminimum side effects. These agents may also be useful in otherconditions with disrupted cholinergic neurotransmission such as tardivedyskinesia, Pick's disease, Huntington's chorea, Freiderich's ataxia,Gilles de la Tourette disease, Down's syndrome, attention-deficitdisorder (ADD), multi-infarct dementia, and age-related cognitivedecline (ARCD).

[0209] The compounds of this invention may also be used in combinationwith a peripheral anti-muscarinic agent such as N-methyl-scopolamine tominimize peripheral side effects; in combination with anti-depressantssuch as imipramine in order to treat both the cognitive decline anddepression associated with AD; in combination with serotonin uptakeinhibitors such as Zoloft® (trademark) to treat both the cognitivedecline and depression associated with AD in combination withantipsychotics such as haloperidol to treat both the cognitive declineand psychosis associated with AD; in combination with anxiolytics suchas diazepam to treat both the cognitive decline and anxiety associatedwith AD; in combination with nicotinic agonists such as nicotine inorder to stimulate both central muscarinic and nicotinic receptors; incombination with neurotrophic factors such as NGF in order to maximizecholinergic enhancement; in combination with agents which slow or arrestAD such as amyloid or tau inhibitors. These agents may also be useful inthe treatment of addictions such as smoking (for cessation) and for thetreatment of glaucoma.

[0210] The compounds of this invention may not only offer palliativetherapy for AD, but may also slow the progression of the disease. Invitro studies have demonstrated that stimulation of the m₁ and m₃muscarinic receptors with carbachol, a known muscarinic agonist, resultsin the rapid release of soluble amyloid precursor protein (APP)derivatives (Nitsch et al., Release of Alzheimer Amyloid PrecursorDerivatives Stimulated by Activation of Muscarinic AcetylcholineReceptors, Science, 258, 304-307 (1992)). Formation of the highlyinsoluble Aβ peptide from APP leads to amyloidosis, resulting inneurotoxicity and the formation of neuritic plaques.

[0211] Activity of the compounds of formula I for muscarinic receptorscan be determined according to the following protocol. Chinese hamsterovary cells (CHO-K1) stably transformed to express human ml -m5receptors can be obtained from Dr. Tom Bonner (Laboratory of CellBiology, National Institute of Mental Health, Building 36, Rm 3A-17,National Institute of Health, Bethesda, Md. 20892). Cells are maintainedin Dulbecco's Modified Eagle Medium containing 10% fetal calf serum andharvested at confluence by brief incubation in Ca⁺⁺/Mg⁺⁺-freephosphate-buffered saline containing 4 mM EDTA.

[0212] For ligand binding studies, cells are homogenized by sonicationin distilled water and membranes are collected by centrifugation (10minutes at 15,000×g). Membranes are incubated 45 minutes at 20-22° C.with ³H-N-methylscopolamine (NMS; 0.5-1.0 nM) in 0.25 ml 20 mM HEPES(N-2-hydroxyethylpiperazine-N′-2-ethane sulfonic acid), 2 mM MgCl₂, pH7.4. Bound ligand is collected by rapid filtration and quantified byliquid scintillation spectroscopy. Non-specific binding is defined inthe presence of 10 μM unlabeled NMS. Apparent Ki for competing ligandsis calculated as described by Cheng and Prusoff, Biochem. Pharm., 22,3099-3108 (1973).

[0213] Functional responses at m2 and m4 receptors can be determined bymeasuring inhibition of forskolin-stimulated cAMP accumulation.Harvested cells are preincubated (15 minutes at 20-22° C.) with3-isobutyl-1-methyl-xanthine (IBMX; 0.2 mM) and then incubated (10minutes at 20-22° C.) in a HEPES-buffered Krebs solution with testcompounds in the presence of 5 μM forskolin. The reaction is stopped bythe addition of 10 N acetic acid and the cAMP content of driedsupernatants is determined using a scintillation proximity assay(Amersham). Carbachol is used as the standard agonist, typicallyproviding 60-80% inhibition of the forskolin-stimulated cAMP levels.

[0214] Functional responses at m₁, m₃ and m₅ receptors can be determinedby measuring increases in phosphotidylinositol hydrolysis. Harvestedcells are preincubated (60 minutes at 37° C.) in HEPES-buffered Krebswith ³H-myoinositol (ARC Inc.; 7.3 μCi/ml). Labelled cells are added totest compounds and incubated 1 hour at 37° C. in the presence of 10 mMLiCl. Cells are extracted with chloroform:methanol (1:2) and the aqueousphase is loaded onto columns of DOWEX AG1-X8 ion exchange resin.Inositol phosphates (mainly IP3) are eluted with 0.1 M formic acid/1 Mammonium formate and counted.

[0215] All of the compounds of this invention, which were tested in theabove functional assays, have EC₅₀ in the m₂ and m₄ receptor assay ofabout 1 nM to about 10 μM or less. All of the compounds of thisinvention, which were tested, have EC₅₀ in the m1, m3 and m5 receptorassay of about 1 picoM to about 10 μM or less.

[0216] The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation.

[0217] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbid acid).

[0218] For buccal administration, the composition may take the form oftablets or lozenges formulated in conventional manner.

[0219] The compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

[0220] The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

[0221] A proposed dose of the active compounds of the invention fororal, parenteral or buccal administration to the average adult human forthe treatment of the conditions referred to above (e.g., AD) is 0.1 to200 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

[0222] Aerosol formulations for treatment of the conditions referred toabove (e.g., AD) in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains 20 μg to 1000 μg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 100 μg to 10 mg.

[0223] Administration may be several times daily, for example 2, 3, 4 or8 times, giving for example, 1, 2 or 3 doses each time.

[0224] In connection with the use of an active compound of thisinvention with a 5-HT re-uptake inhibitor, preferably sertraline, forthe treatment of subjects possessing any of the above conditions, it isto be noted that these compounds may be administered either alone or incombination with pharmaceutically acceptable carriers by either of theroutes previously indicated, and that such administration can be carriedout in both single and multiple dosages. More particularly, the activecombination can be administered in a wide variety of different dosageforms, i.e., they may be combined with variouspharmaceutically-acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hand candies, powders, sprays, aqueoussuspension, injectable solutions, elixirs, syrups, and the like. Suchcarriers include solid diluents or fillers, sterile aqueous media andvarious non-toxic organic solvents, etc. Moreover, such oralpharmaceutical formulations can be suitably sweetened and/or flavored bymeans of various agents of the type commonly employed for such purposes.In general, the compounds of formula I are present in such dosage formsat concentration levels ranging from about 0.5% to about 90% by weightof the total composition, i.e., in amounts which are sufficient toprovide the desired unit dosage and a 5-HT re-uptake inhibitor,preferably sertraline, is present in such dosage forms at concentrationlevels ranging from about 0.5% to about 90% by weight of the totalcomposition, i.e., in amounts which are sufficient to provide thedesired unit dosage. The compounds of this invention may exist indifferent polymorphic forms, i.e., different crystalline forms.

[0225] A proposed daily dose of an active compound of this invention inthe combination formulation (a formulation containing an active compoundof this invention and a 5-HT re-uptake inhibitor) for oral, parenteral,rectal or buccal administration to the average adult human for thetreatment of the conditions referred to above is from about 0.01 mg. toabout 2000 mg., preferably from about 0.1 mg. to about 200 mg of theactive ingredient of formula I per unit dose which could beadministered, for example, 1 to 4 times per day.

[0226] A proposed daily dose of a 5-HT re-uptake inhibitor, preferablysertraline, in the combination formulation for oral, parenteral orbuccal administration to the average adult human for the treatment ofthe conditions referred to above is from about 0.1 mg. to about 2000mg., preferably from about 1 mg. to about 200 mg. of the 5-HT re-uptakeinhibitor per unit dose which could be administered, for example, 1 to 4times per day.

[0227] A preferred dose ratio of sertraline to an active compound ofthis invention in the combination formulation for oral, parenteral orbuccal administration to the average adult human for the treatment ofthe conditions referred to above is from about 0.00005 to about 20,000,preferably from about 0.25 to about 2,000.

[0228] Aerosol combination formulations for treatment of the conditionsreferred to above in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains from about 0.01 μgto about 10,000 μg of the active compound of this invention, preferablyfrom about 1 μg. to about 10 mg. of such compound. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

[0229] Aerosol formulations for treatment of the conditions referred toabove in the average adult human are preferably arranged so that eachmetered dose or “puff” of aerosol contains from about 0.01 mg. to about2000 mg. of a 5-HT re-uptake inhibitor, preferably sertraline,preferably from about 1 mg. to about 200 mg of sertraline.Administration may be several times daily, for example 2, 3, 4 or 8times, giving for example, 1, 2 or 3 doses each time.

[0230] As previously indicated, a 5-HT re-uptake inhibitor, preferablysertraline, in combination with compounds of formula I are readilyadapted to therapeutic use as antidepressant agents. In general, theseantidepressant compositions containing a 5-HT re-uptake inhibitor,preferably sertraline, and a compound of formula I are normallyadministered in dosages ranging from about 0.01 mg. to about 100 mg. perkg. of body weight per day of a 5-HT re-uptake inhibitor, preferablysertraline, preferably from about 0.1 mg. to about 10 mg. per kg. ofbody weight per day of sertraline; with from about 0.001 mg. to about100 mg. per kg. of body weight per day of a compound of formula 1,preferably from about 0.01 mg. to about 10 mg. per kg. of body weightper day of a compound of formula 1, although variations will necessarilyoccur depending upon the conditions of the subject being treated and theparticular route of administration chosen.

[0231] The following Examples illustrate the preparation of thecompounds of the present invention. Commercial reagents were utilizedwithout further purification. Melting points are uncorrected. NMR dataare reported in parts per million (d) and are referenced to thedeuterium lock signal from the sample solvent. Specific rotations weremeasured at room temperature using the sodium D line (589 nm). Roomtemperature refers to 20-25° C. Mass spectrum (MS) and high resolutionmass spectrum (HRMS) were performed using electron impact (EI, 70 eV),chemical ionization (CI) or fast atom bombardment (FAB) conditions.Chromatography refers to column chromatography performed using 32-63 μmsilica gel and executed under nitrogen pressure (flash chromatography)conditions. Purification of final compounds was carried out usingbuffered silica gel prepared as follows. A mixture of 125 grams ofsilica gel and 500 mL of 4% KH₂PO₄ was stirred for 1 hour and filtered.The buffered silica gel collected was air-dried and then dried in theoven at 120° C. for 48 hours or more.

EXAMPLE 1 Scheme 1N-Phenyl-N′-(phenylimino-pyrrolidin-1-yl-methyl)-benzamidine Step AIntermediate of Formula II (Z=Phenyl, X=Pyrrolidine)

[0232] A solution of pyrrolidine (8.18 g, 0.115 mol) and triethylamine(11.6 g, 0.115 mol) in diethyl ether (20 mL) was added dropwise to acold (0° C.) solution of phenyl isocyanide dichloride (20.0 g, 0.115mol) in diethyl ether (200 mL). After addition was complete, the mixturewas stirred at 0° C. for 1 hour and then allowed to warm to roomtemperature (20 minutes). The reaction was filtered and the filtrate wasadded dropwise to a saturated solution of ammonia/isopropanol (600 mL).After 1.25 hours, excess ammonium chloride was removed by filtration andthe filtrate was concentrated. The residue was redissolved inisopropanol (250 mL) and hydrogen chloride (g) was bubbled through for 5minutes. After concentration, the pale yellow gum was triturated fromdiethyl ether to yield an off-white solid (24.20 g, 93%), hydrochloridesalt.

[0233]¹H-NMR (DMSO-d₆) δ9.68 (s, 1H), 7.59 (s, 2H), 7.43 (m, 2H), 7.30(m, 3H), 3.52 (br m, 4H), 1.93 (br t, 4H, J=6.6Hz).

Step B N-Phenyl-N′-(phenylimino-pyrrolidin-1-yl-methyl)-benzamidine

[0234] Sodium hydride (60% mineral oil dispersion, 1.1 g, 27.68 mmol)was added to a suspension of the product from Step A (free base, 6.25 g,27.68 mmol) in tetra-hydrofuran, THF, (70 mL) at room temperature. Afterstirring for 15 minutes, the mixture was cooled to 0° C. and a solutionof benzene carboxyimidoyl chloride, N-phenyl, (prepared according to themethod described in J. Heterocyclic Chem.,18, 651 (1981)) (3.0 g, 13.84mmol) in THF (50 mL) was added dropwise. The resulting mixture wasallowed to warm to room temperature and was stirred for 16 hours(overnight). The reaction mixture was then heated to reflux for 2 hours.After cooling to room temperature, the mixture was filtered and thefiltrate concentrated. The residue was dissolved in chloroform and theresulting organic layer was washed with 1 N hydrochloric acid, followedby brine. The organic layer was then dried over potassium carbonate,filtered, and concentrated. The yellow soft solid obtained was dissolvedin a minimum amount of acetone and diethyl ether was added. The paleyellow solid obtained was collected by filtration and dried under highvacuum to give 1.8 grams of crude material. Further purification wasachieved by recrystallization (isopropanol/diethyl ether) to give thetitle compound (400 mg, 7%), hydrochloride salt, as an off-white solid.

[0235] Mp 246-247° C.; ¹H-NMR (DMSO-d₆) δ10.78 (s, 1H), 10.20 (s, 1H),7.75 (br s, 2H), 7.56 (t, 1H, J=7.4 Hz), 7.40-7.47 (m, 4H), 7.11-7.27(m, 4H), 7.06 (d, 2H, J=7.5 Hz), 6.84 (d, 2H, J=7.3 Hz), 3.63 (br s,4H), 1.97 (br, s, 4H); CIMS C₂₄H₂₄N⁴:369 [(M+1)⁺, 100].

EXAMPLE 2 Scheme 2N-(4-Fluoro-phenyl)-N′-(phenylimino-pyrrolidin-1-yl-methyl)-benzamidineStep A Intermediate of Formula V (X=pyrrolidine: Z═R₃=Phenyl)

[0236] A solution of pyrrolidine (0.55 mL, 6.61 mmol) and triethylamine(0.92 mL, 6.61 mmol) in diethyl ether (10 mL) was added dropwise to acold (0° C.) solution of phenyl isocyanide dichloride (0.9 mL, 6.61mmol) in diethyl ether (1 5 mL). After 40 minutes, the reaction wasfiltered. The filtrate was re-cooled to 0° C. and a solution of benzenecarboximidothioic acid, methyl ester (prepared according to the methodsdescribed in Eur. J. Med. Chem., Chim. Ther., 12, 365 (1977), andAustralian J. Chem., 30, 2225 (1977)) (1.0 g, 6.61 mmol) in diethylether (5 mL) was added. The ice bath was removed and the mixture washeated to reflux for 19 hours. Solids were removed by filtration and thefiltrate was concentrated. The residue obtained was washed with diethylether to yield (1.77 g, 76%) an off-white solid, hydrochloride salt.

[0237]¹H-NMR (DMSO-d₆) δ10.83 (s, 1H), 7.60 (t, 1H, J=7.5 Hz), 7.46 (t,2H, J=7.7 Hz), 7.18-7.32 (m, 3H), 7.04 (d, 2H, J=7.5 Hz), 6.87 (d, 2H,J=6.9 Hz), 3.73-3.78 (m, 2H), 3.40-3.57 (m, 2H), 2.58 (s, 3H), 1.95-2.11(m, 4H).

Step BN-(4-Fluoro-phenyl)-N′-(phenylimino-pyrrolidin-1-yl-methyl)-benzamidine

[0238] A mixture of the product from Step A (0.5 g, 1.39 mmol) andp-fluoroaniline (0.330 mL) in dioxane (10 mL) was heated to reflux for23 hours. The mixture was allowed to cool to room temperature and thereaction was filtered. The title compound (0.453 g, 77%), hydrochloridesalt, was obtained as a white solid.

[0239] Mp 259-260° C. (dec); ¹H-NMR (DMSO-d₆) δ10.68 (s, 1H), 9.95 (s,1H), 7.77 (br s, 2H), 7.57 (t, 1H, J=7.4 Hz), 7.42 (t, 2H, J=7.6 Hz),7.29 (t, 2H, J=8.7 Hz), 7.12-7.23 (m, 3H), 7.04 (d, 2H, J=7.6 Hz), 6.77(d, 2H, J=7.2 Hz), 3.57-3.64 (m, 4H), 1.97-1.99 (m, 4H); FABMSC₂₄H₂₃FN₄: 387 [(M+1)⁺, 100].

EXAMPLE 3 (Scheme 3)N-[(2-Methyl-piperidin-1-yl)-phenylimino-methyl]-N′-phenyl-benzamidineStep A Intermediate of Formula VIII (Z═R₂═R₃=phenyl)

[0240] A solution of sodium thiocyanate (18.8 g, 0.32 mol) in acetone(400 mL) was added dropwise to a stirring solution of benzenecarboxyimidoyl chloride, N-phenyl (50.0 g, 0.32 mol) in acetone (120 mL)at 0° C. After 1 hour, the reaction mixture was filtered (10-20 p) andthe filtrate was re-cooled to 0° C. Aniline (23.7 mL, 0.232 mol) wasadded dropwise and the reaction was allowed to warm to room temperature.After 1.5 hours, the precipitate formed was collected by filtration toyield a pale yellow solid (49.12 g, 64%).

[0241]¹H-NMR (DMSO-d₆) δ10.61-10.88 (m, 1H), 9.80-10.21 (m, 1H),7.40-7.75 (m, 9H), 7.21-7.38 (m, 4H), 6.97-7.15 (m, 2H)

Step B Intermediate of Formula VII (Z═R₂═R₃=phenyl)

[0242] Methyl iodide (6.8 mL, 0.11 mol) was added to a suspension of theproduct from Step A (33.0 g, 0.1 mol) in methylene chloride (450 mL) atroom temperature and then the reaction was heated to reflux for 22hours. The reaction mixture was then cooled, filtered and theprecipitate collected and dried to yield a pale yellow solid (27.7 g,59%) as the hydroiodide salt.

[0243]¹H-NMR (DMSO-d₆) δ11.70 (br s, 2H), 7.63-7.71 (m, 6H), 7.51 (t,3H, J=7.8 Hz), 7.32-7.43 (m, 4H), 7.05-7.15 (m, 2H), 2.5 (s, 3H).

Step CN-[(2-Methyl-piperidin-1-yl)-phenylimino-methyl]-N′-phenyl-benzamidine

[0244] To a suspension of the product from Step B (1.00 g, 2.11 mmol) in1,4-dioxane (20 mL) was added 2-methylpiperidine (0.745 mL, 6.33 mmol).The resulting solution was heated to reflux for 20 hours. The reactionwas then concentrated and the residue purified by silica gel flashchromatography (gradient of 100% methylene chloride to 5%methanol-methylene chloride) to give the title compound (0.1939, 17%),hydroiodide salt, as a pale yellow solid.

[0245] Mp 219-221° C. (dec); ¹H-NMR (DMSO-d₆) 10.57 (br s, 1H), 9.64 (brs, 1H), 7.69-7.72 (m, 2H), 7.61 (t, 1H, J=7.7 Hz), 7.43-7.51 (m, 4H),7.11-7.29 (m, 4H), 6.98 (d, 2H), 6.74 (d, 2H), 4.51-4.60 (m. 1H),3.95-4.09 (m, 1H), 3.25-3.34 (m, 1H), 1.40-1.73 (m, 5H), 1.28 (br d, 3H,J=5.3 Hz); CIMS C₂₆H₂₈N₄: 397 [(M+1)⁺, 100].

EXAMPLE 4 (Scheme 3)N-([1,2]Oxazinan-2-yl-phenylimino-methyl)-N′-phenyl-benzamidine Step C′

[0246] Triethylamine (0.20 mL, 1.45 mmol) followed by tetrahydrooxazine(prepared according to the methods described in King, H., J. Chem. Soc.1942, 432) (0.358 g, 2.90 mmol) was added to a solution of the productfrom Example 3, Step B, free base, (0.5 g, 1.45 mmol) in acetonitrile(50 mL) at 0° C. A solution of silver nitrate (0.246 g, 1.45 mmol) inacetonitrile (2 mL) was added and, after 10 minutes, the ice bath wasremoved and the reaction allowed to stir at room temperature in thedark. After 1.5 hours, the mixture was centrifuged (3500 rpm, 10minutes) and the supernatant was decanted, filtered (45μ), andconcentrated. Purification by flash chromatography (gradient of 100%methylene chloride to 1 5% methanol-methylene chloride) gave the titleproduct (0.524 g, 86%), nitrate salt, as an off-white solid.

[0247] Mp 187-190° C.; ¹H-NMR (DMSO-d₆) δ10.90 (br s, 1H), 10.45 (br s,1H), 7.70-7.74 (m, 2H), 7.62 (t, 1H, J=7.5 Hz), 7.43-7.52 (m, 4H),7.23-7.31 (m, 4H), 7.10 (d, 2H, J=7.8 Hz), 6.95 (d, 2H, J=7.4 Hz),3.82-4.20 (m, 4H), 1.48-1.80 (m, 4H); CIMS C₂₄H₂₄N₄O: 385 [(M+1)⁺, 100].

EXAMPLE 5 (Scheme 3)N-(4-Methoxy-phenyl)-2,6-dimethyl-N′-[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-benzamidineStep A′ Intermediate of Formula IV (R₂=(4)-methoxyphenyl:R₃=2,6-Dimethylphenyl)

[0248] A neat mixture of 2,6-dimethylbenzamide, N-4-methoxyphenyl (6.60g, 25.85 mmol) and phosphorous pentachloride (5.38 g, 25.85) was heatedto 120° C. The solution obtained was stirred for 20 minutes. Toluene wasadded and the mixture was concentrated (twice). The oil obtained wasimmediately used as such in the next step.

Step A Intermediate of Formula VIII (R₂=(4)-methoxyphenyl:R₃=2,6-Dimethyl phenyl: Z=phenyl)

[0249] The same procedure described in Example 3, Step A above wasfollowed with sodium thiocyanate (2.10 g, 25.85 mmol), the product fromStep A′ (crude, 25.85 mmol), and aniline (3.53 mL, 38.78 mmol) to yielda white solid (1.75 g, 18%).

[0250]¹H-NMR (CDCl₃) δ7.80-7.84 (m, 3H,), 7.42 (t, 2H, J=7.9 Hz),7.18-7.28 (m, 2H), 7.02 (d, 2H, J=7.7 Hz), 6.67 (s, 4H), 3.71 (s, 3H),2.29 (s, 6H).

N-(4-Methoxy-phenyl)-2.6dimethyl-N′-[(2-methyl-piperidin-1-yl)-phenylimino-methyl]-benzamidineStep C″

[0251] To a solution of the product from Step A, above, (0.50 g, 1.28mmol) in dimethylformamide (6 mL) was added 2-methylpiperidine (0.33 g,2.82 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,hydrochloride (EDCl) (0.27 g, 1.41 mmol). The resulting mixture wasstirred at room temperature for 16 hours (overnight). The reaction wasconcentrated in vacuo and the residue was partitioned between ethylacetate and saturated sodium bicarbonate. The separated organic layerwas dried (potassium carbonate), filtered, and ethanolic hydrogenchloride was added. After concentration, the residue was purified bysilica gel flash chromatography (gradient from 100% methylene chlorideto 15% methanol-methylene chloride) gave the title compound (0.475 g,76%), hydrochloride salt, as a white solid.

[0252] Mp 190-192° C. (dec); ¹H-NMR (CDCl₃) δ7.52 (d, 2H, J=7.6 Hz),7.27 (t, 2H, J=7.3 Hz), 7.16 (t, 1H, J=7.4 Hz), 7.03 (t, 1H, J=7.6 Hz),6.83 (d, 1H, J=7.1 Hz), 6.76 (d, 1H, J=7.5 Hz), 6.68 (d, 2H, J=9.0 Hz),6.51 (d, 2H, J=9.0 Hz), 4.90 (br s, 1H), 4.32 (br d, 1H, J=13.6 Hz),1.62-1.95 (m, 5H), 1.53 (d, 3H, J=7.0 Hz), 1.30-1.41 (m, 2H); CIMSC₂₉H34N₄O: 455 [(M+1)⁺, 100].

EXAMPLE 6 (Scheme 4)(3-Phenylimino-3-[2-methyl]piperidin-1-yl-1-o-tolyl-propenyl)-(4-fluoro-phenyl)-amineStep A Intermediate of Formula XI (R₃=2-Methylphenyl: Z=phenyl)

[0253] A solution of lithium bis(trimethylsilyl)amide (1M intetrahydrofuran, 22.36 mL, 22.36 mmol) was added to a solution of2-methyl acetophenone (3.0 g, 22.36 mmol) in tetrahydrofuran (220 mL) at−78° C. After 15 minutes, phenyl isocyanide (2.67 mL, 22.36 mmol) wasadded and the resulting mixture was kept at −78° C. for 0.5 hour andthen at room temperature overnight. To the reaction was added 1Nhydrochloric acid and the mixture was extracted with methylene chloride.The separated organic layer was dried (potassium carbonate), filtered,and concentrated. The residue was purified by flash chromatography (5%ethyl acetate-hexane) to yield a bright yellow solid (4.14 g, 69%).

[0254]¹H-NMR (CDCl₃) (2:1 mixture of tautomers) δ14.79 (s, 1H), 10.87(br s, 0.5H), 8.21 (s, 1H), 7.92 (d, 0.5H, J=8.1 Hz), 7.80 (d, 1H, J=7.7Hz), 7.16-7.49 (m, 12H), 5.80 (s, 1H). 4.56 (s, 1H), 2.57 (s, 1.5H),2.44 (s, 3H).

Step B Intermediate of Formula X (R₂=4-Fluorophenyl: R₃=2-Methylphenyl:Z=phenyl)

[0255] A mixture of the product of Step A above (3.0 g, 11.14 mmol),4-fluoroaniline (1.16 mL, 12.25 mmol), and 4-fluoroaniline hydrochloride(0.164 g, 1.11 mmol) in benzene (100 mL) was heated to reflux withremoval of water (Dean-Stark trap). After 18 hours, additional4-fluoroaniline (0.264 mL, 2.79 mmol), and 4-fluoroaniline hydrochloride(0.164 g, 1.11 mmol) were added. Reflux was continued for another 30hours (48 hours total reaction time). The mixture was concentrated andthe residue was triturated from diethyl ether to give a yellow solid.This solid was redissolved in methylene chloride and the organic layerwas washed with brine, dried (potassium carbonate), filtered, andconcentrated to yield a yellow solid (1.93 g, 48%).

[0256]¹H-NMR (CDCl₃) δ13.65 (s, 1H), 7.97 (s, 1H), 7.15-7.40 (m, 8H),7.07 (d, 1H, J=7.3 Hz), 6.65-6.82 (m, 4H), 5.43 (s, 1H), 2.11 (s, 3H).

Step C Intermediate of Formula IX (R₂=4-Fluorophenyl: R₃=2-Methylphenyl:Z=phenyl)

[0257] Trimethyloxonium tetrafluoroborate (0.673 g, 4.55 mmol) was addedto a solution of the product from Step B, above, (1.50 g, 4.14 mmol) inmethylene chloride (50 mL) at 0° C. After 15 minutes, the ice bath wasremoved and the reaction was allowed to stir at room temperature for1.25 hours. The reaction mixture was washed with saturated potassiumcarbonate and the separated organic layer was dried (potassiumcarbonate), filtered, and concentrated. The residue was purified byflash chromatrography (methylene chloride) to yield a white foam (1.28g, 82%).

[0258] Mp 179-181° C.; ¹H-NMR (CDCl₃) δ12.47 (s, 1H), 7.22-7.41 (m, 5H),7.12-7.14 (m, 2H), 7.04 (d, 2H, J=7.7 Hz), 6.71 (t, 2H, J=8.7 Hz),6.54-6.56 (m, 2H), 5.02 (s, 1H), 2.35 (s, 3H), 2.18 (s, 3H); CIMS 428[(M+1)⁺, 100].

Step D (3-Phenylimino-3-[2-methyl]piperidin-1-yl-1o-tolyl-propenyl)-(4-fluoro-phenyl)-amine

[0259] The same procedure described in Example 4C′ was followed with theproduct from Step C, above, (0.40 g, 1.06 mmol), 2-methylpiperidine (0.187 mL, 1.59 mmol), triethylamine (0.147 mL, 1.06 mmol), and silvernitrate (0.180 g, 1.06 mmol) in acetonitrile (20 mL) to give the titlecompound (0.395 g, 76%), nitrate salt, as a pale yellow solid.

[0260]¹H-NMR (CDCl₃) δ10.35 (br s, 1H), 8.95 (br s, 1H), 7.33 (d, 2H,J=7.5 Hz), 6.99-7.22 (m, 6H), 6.93 (d, 1H, J=7.2 Hz), 6.54 (t, 2H, J=8.7Hz), 6.13 (dd, 2H, J=9.0 Hz, J=4.7 Hz), 4.57-4.72 (m, 1H), 4.52 (s, 1H),4.10-4.22 (m, 1H), 3.41-3.58 (m, 1H), 1.96 (s, 3H), 1.62-1.95 (m, 6H)1.44 (br d, 3H, J=6.3 Hz), CIMS C₂₈H₃₀FN₃: 428 [(M+1)⁺, 100].

EXAMPLE 7 (Scheme 5)N-[Cyclohexylimino-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6dimethyl-benzamidineStep A Intermediate of Formula XIV (R₂=4-fluorophenyl:R₃=2,6dimethylphenyl)

[0261] A neat mixture of 2,6-dimethylbenzamide, N-4-fluorophenyl (6.60g, 25.85 mmol) and phosphorous pentachloride (5.38 g, 25.85) was heatedto 120° C. The solution obtained was stirred for 20 minutes. Toluene wasadded and the mixture was concentrated (twice). The oil obtained wasdissolved in toluene (270 mL) and cooled to 0° C. Ammonia(g) was bubbledthrough the reaction mixture for 0.5 hours. The reaction was filteredand the filtrate was concentrated. The residue obtained was purified bysilica gel flash chromatography (gradient from 50% ethyl acetate-hexaneto 100% ethyl acetate) to yield an off-white solid (5.02 g, 56%).

[0262]¹H-NMR (CDCl₃, mixture of rotomers) δ6.99-7.22 (m, 5H), 6.60-6.73(m, 2H), 4.79 (br s, 2H), 2.48 (s, 3H), 2.30 (s, 3H).

Step B Intermediate of Formula XIII (X=2-methylpiperdine:R₃=4fluorophenyl: R₂=2,6-dimethyl)

[0263] Triethylamine (1.2 mL, 8.25 mmol), dimethylaminopyridine (0.10 g,0.825 mmol), and the product from Step A (2.0 g, 8.25 mmol) were addedto a solution of 2-methylpiperidine carbamoyl chloride (preparedaccording to the method of Rost et al., J. Am. Pharm. Assoc., 46, 290(1957)) (1.33 g, 8.25 mmol) in methylene chloride. The resulting mixturewas allowed to stir at room temperature for 4 days. The mixture waswashed with saturated potassium carbonate, dried (potassium carbonate),filtered, and concentrated. Purification by flash chromatography(gradient from 10% ethyl acetate-hexane to 100% ethyl acetate) yielded awhite foamy solid (0.832 g, 28%).

[0264]¹H-NMR (CDCl₃, mixture of rotomers) δ7.15 (t, 1H, J=7.6 Hz), 6.97(br t, 2H, J=9.8 Hz), 6.76 (t, 2H, J=8.6 Hz), 6.60-6.64 (m, 2H),4.32-5.15 (m, 2H), 2.80-3.02 (m, 1H), 2.28 (s, 3H), 2.21 (s, 3H),1.40-1.75 (m, 6H), 1.12-1.3 (m, 3H).

Step CN-[Cyclohexylimino-(2-methyl-piperidin-1-yl)-methyl]-N′-(4-fluoro-phenyl)-2,6dimethyl-benzamidine

[0265] A neat mixture of the product from Step B (0.20 g, 0.544 mmol)and phosphorous pentachloride (0.113 g, 0.544 mmol) was heated to 125°C. and the melt obtained was stirred for 1 hour. Toluene was added andthe mixture was concentrated (twice). The residue was dissolved intetrahydrofuran (8 mL) and cyclohexylamine (0.27 g, 2.72 mmol) wasadded. The mixture obtained was stirred at room temperature for 2 hours.The reaction was filtered and the filtrate was concentrated. The residuewas purified by silica gel flash chromatography (gradient of 100%methylene chloride to 5% methanol-methylene chloride) to give the titlecompound (0.084 g, 34%), hydrochloride salt, as a white solid.

[0266] Mp 167-168° C.; ¹H-NMR (CDCl₃, mixture of rotomers) δ510.90 (brs, 1H), 7.17-7.27 (m, 2H), 6.93-7.06 (m, 3H), 6.76 (t, 2H, J=8.5 Hz),4.60-4.75 (m, 1H), 4.03-4.14 (m, 1H), 3.70-3.85 (m, 1H), 3.38-3.51 (m,1H), 2.42 (s, 3H), 2.27 (s, 3H), 1.96-2.17 (m, 2H), 1.40-1.80 (m,14H), 1. 17-1.37 (m, 3H); EIMS C₂₈H₃₇FN₄: 448 (M⁺).

EXAMPLE 8N-(4-Fluoro-phenyl)-2-methyl-N′-[(4oxo-piperidin-1-yl)-phenylimino-methyl]-benzamidine

[0267] The procedure described in Example 5, Step C″, was followed witha compound of the formula VII (wherein R₂=4-fluorophenyl;R₃=2-methylphenyl; Z=phenyl) (0.40 g, 1.10 mmol),1,4-dioxa-8-azaspiro[4.5]decane (0.347 g, 2.42 mmol), and EDCl (0.232 g,1.21 mmol) in dimethylformamide (6 mL) to yieldN-[(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)phenylimino-methyl]-N′-(4-fluorophenyl)-2-methyl benzamidine (0.388 g, 69%) as a white solid.

[0268]¹H-NMR (DMSO-d₆) δ10.58 (br s, 1H), 10. 15 (br s, 1H), 7.78-7.87(m, 2H), 7.11-7.48 (m, 8H), 6.91 (d, 1H, J=6.3 Hz), 6.81 (d, 2H, J=7.0Hz) 3.95 (s, 4H), 3.77 (br s, 4H), 1.79 (brs, 4H), 1.66 (s, 3H).

[0269] A solution of the above product (0.350 g, 0.688 mmol) in 90%trifluoroacetic acid/water (8 mL) was stirred at room temperature for5.75 hours. The solution was concentrated and the residue waspartitioned between methylene chloride and saturated potassiumcarbonate. The organic layer was dried (potassium carbonate), filtered,and concentrated. The residue was converted to the hydrochloride salt bydissolving in diethyl ether and bubbling hydrogen chloride (g). Theprecipitate obtained was collected and dried to give the title compound(0.262 g, 82%), hydrochloride salt, as an off-white solid.

[0270] Mp 234-235° C.; ¹H-NMR (DMSO-d₆) δ10.63 (s, 1H), 10.22 (s, 1H),7.79-7.88 (m, 2H), 7.45 (t, 1H, J=7.4 Hz), 7.13-7.39 (m, 7H), 6.93 (d,1H, J=7.4 Hz), 6.83 (d, 2H, J=7.9 Hz), 3.90-4.12 (m, 4H) 2.65 (t, 4H,J=5.8 Hz), 1.63 (s, 3H); CIMS C₂₆H₂₅FN₄O: 429 [(M+1)⁺, 100].

EXAMPLE 9N-(4-Fluoro-phenyl)-N′-[(4-hydroxy-piperidin-1-yl)-phenylimino-methyl]-2,6dimethyl-benzamidine

[0271] Sodium borohydride (0.006 g, 0.152 mmol) was added to a solutionof the product from Example 8, free base, (0.067 g, 0.152 mmol) inethanol (6 mL) and the mixture was stirred at room temperature for 2hours. Saturated ammonium chloride was added and the mixture wasextracted with methylene chloride (twice). The organic layer was dried(potassium carbonate), filtered, and concentrated. The residue wasdissolved in dioxane and hydrogen chloride (g) was bubbled through.After removal of volatiles, the salt obtained was purified by silica gelflash chromatography to give the title compound (0.033 g, 45%),hydrochloride salt, as an off-white solid.

[0272] Mp 163-165° C.; ¹H-NMR (CDCl₃, mixture of rotomers) δ7.48 (d, 2H,J=7.2 Hz), 7.29-7.34 (m, 3H), 7.06 (t, 1H, J=7.6 Hz), 6.82 (d, 2H, J=7.6Hz), 6.62-6.79 (m, 4H) 4.10-4.36 (m, 3H), 3.73-3.98 (m, 2H), 1.91-2.22(m, 6H), 1.60-1.81 (m, 4H); CIMS C₂₇H₂₉FN₄O: 445 [(M+1)⁺, 100].

EXAMPLE 10N-(4-Hydroxy-phenyl)-2,6-dimethyl-N′-[2-methyl-piperdin-1-yl)-phenylimino-methyl]-benzamidine

[0273] A solution of the product from Example 5, Step C″ (0.04 g, 0.081mmol) in 48% aqueous hydrobromic acid (3 mL) was heated to 110° C. for 4hours. The cooled reaction mixture was made basic by addition ofsaturated sodium bicarbonate. The resulting mixture was extracted withmethylene chloride and the separated organic layer was dried (potassiumcarbonate), filtered, and concentrated. Ethanolic hydrogen chloride wasadded to the residue and after stirring for 15 minutes, volatiles wereremoved under reduced pressure. The salt obtained was triturated fromdiethyl ether to give the title compound (0.034 g, 87%), hydrochloridesalt, as a pale yellow solid.

[0274] Mp 216-218° C.; ¹H-NMR (DMSO-d₆, mixture of rotomers) 10.60 (s,1H), 9.53 (s, 1H), 7.51 (d, 2H, J=8.5 Hz), 7.36-7.45 (m, 1H), 7.21-7.30(m, 2H) 6.95-7.12 (m, 3H), 6.87 (d, 2H, J=8.7 Hz), 6.70 (d, 2H, J=7.5Hz), 4.41-4.53 (m, 1H), 3.88-4.01 (m, 1H), 3.13-3.28 (m, 1H), 1.95 (s,3H), 1.76 (s, 3H), 1.40-1.73 (m, 6H), 1.19-1.28 (m, 3H); CIMS C₂₈H₃₂N₄O:441 [(M+1)⁺, 100].

EXAMPLE 11 (Scheme 5)N-(4-Fluoro-phenyl)-2-methyl-N′-[(1-methyl-cyclohexyl)-phenylimino-methyl]-benzamidineStep A Intermediate of Formula XIV (R₂=4-fluorophenyl;R₃=2-methylphenyl)

[0275] A neat mixture of 2-methylbenzamide, N-4-fluorophenyl (4.0 g,17.47 mmol) and phosphorous pentachloride (3.64 g, 17.47 mmol) washeated at 1 20° C. for 30 minutes. Toluene was added and the mixture wasconcentrated (twice). The oil obtained was dissolved in diethyl ether(50 mL) and cooled to 0° C. Ammonia (g) was bubbled through the reactionmixture for 20 minutes. The reaction was filtered and the filtrateconcentrated. The residue was purified by silica gel flashchromatography (gradient from 100% chloroform to 5% methanol-chloroform)to yield a white solid (1.31 g, 33%).

[0276]¹H NMR (CDCl₃) δ7.45-7.47 (m, 1H), 7.22-7.25 (m, 2H), 7.00-7.09(m, 2H), 6.91-6.98 (m, 2H), 6.74-6.78 (m, 1H), 4.71-4.74 (br s, 2H),2.53 (br s, 3H).

Step BN-(4-Fluoro-phenyl)-2-methyl-N′-[(1-methyl-cyclohexyl)-phenylimino-methyl]-benzamidine

[0277] A neat mixture of 1-methyl-cyclohexylcarboxamide, N-phenyl (0.22g, 1.0 mmol) and phosphorous pentachloride (0.21 g, 1.0 mmol) was heatedat 120° C. for 40 minutes. Toluene was then added and the mixture wasconcentrated (twice). The residue was dissolved in tetrahydrofuran (10mL) and the product from Step A (0.46 g, 2 mmol) was added. The reactionwas stirred at room temperature for 18 hours. The mixture was thenfiltered and the filtrate concentrated. Purification by flashchromatography (chloroform) yielded the title compound (0.22 g, 52%) asa white solid.

[0278] Mp 210-211° C.; ¹H NMR (CDCl₃) 7.26 (t, 2H, J=8 Hz), 6.88-7.14(m, 7H), 6.70 (t, 2H, J=8 Hz), 6.43-6.46 (m, 2H), 2.02-2.14 (m, 1H),1.44-1.65 (m, 12H), 1.33 (s, 3H); EIMS C₂₈H₃₀FN₃:427 (M⁺). TABLE 1 R² R³Method (yield Y X Z (phenyl) (phenyl) %)^(i) mp(° C.) MS^(h) 12 Npiperidine^(f) phenyl H H Ex 3 (17)^(a) 198-200 383 (FAB) (d) 13 Nthiomorpholine^(f) phenyl H H Ex 3 216-218 401 (FAB) (17)^(b) (d) 14 Ndiethylamine^(f) phenyl H H Ex 3 (21)^(b) 222-224 371 (FAB) (d) 15 Npyrrolidine phenyl 4-methoxy H Ex 2 (78)^(a) 244-245 398 (EI) 16 Npyrrolidine phenyl 4-chloro H Ex 2 (82) 219-221 403 (FAB) 17 Nhexamethyleneimine^(f) phenyl H H Ex 3 (60) 228-229 397 (FAB) 18 Nhexamethyleneimine^(f) phenyl 4-methoxy H Ex 2 (70)^(a) 241-243 426 (EI)19 N hexamethyleneimine^(f) phenyl 4-fluoro H Ex 2 (77) >228 (d) 414(EI) 20 N pyrrolidine phenyl H 2-methyl Ex 3 (32)^(b) 191-192 383 (FAB)21 N 4-methyl-piperidine^(f) phenyl H H Ex 3 (22) 192-195 397 (FAB) (d)22 N heptamethyleneimine^(f) phenyl H H Ex (27) 252-253 411 (FAB) (d) 23N 3-methyl-piperidine^(f) phenyl H H Ex 3 (34) 179-182 397 (FAB) (d) 24N 4-hydroxy-piperidine phenyl H 2-methyl Ex 3 (45)^(b) 218-220 413 (FAB)25 N pyrrolidine 4-fluoro- H H Ex 3 (28)^(b) 242-243 387 (CI) phenyl 26N 4-hydroxy-piperidine phenyl 4-fluoro 2-methyl Ex 3 (43)^(b) 228-230431 (FAB) (d) 27 N pyrrolidine 2-fluoro- H H Ex 3 (10)^(b) 254-255 387(FAB) phenyl 28 N 2-methyl-piperidine phenyl 4-fluoro 2-methyl Ex (3(39)^(b) 173-175 429 (CI) 29 N 4-hydroxy-piperidine 2-fluoro- H 2-methylEx 3 (19)^(b) 224-225 430 (EI) phenyl 30 N pyrrolidine phenyl 2-chloro HEx 3 (13)^(b) 228-230 403 (CI) 31 N pyrrolidine^(f) phenyl H 2,6- Ex 3(20)^(b) 255-257 397 (CI) dimethyl 32 N (−)-2-methyl-piperidine^(f,j)phenyl H H Ex 3 (28) 181-183 397 (CI) 33 N (+)-2-methyl- phenyl H H Ex 3(43) 180-182 397 (CI) piperidine^(f,k) 34 N hexamethyleneimine phenyl4-fluoro 2-methyl Ex 3 (55) 240-242 428 (EI) 35 N 2-methyl-piperidinephenyl 4-fluoro 2,6- Ex 3 (28) 181-183 443 (CI) dimethyl 36 N4-hydroxy-piperidine 2-fluoro- 4-fluoro 2-methyl Ex 3 (62) 174-175 448(EI) phenyl 37 N 2-methyl-piperidine phenyl 4-fluoro 2-chloro Ex 4 (70)145-147 449 (CI) 38 N 3-hydroxy-piperidine^(g) phenyl H H Ex 4 (73)189-192 399 (CI) 39 N pyrrolidine^(g) phenyl H 2-fluoro Ex 4 (68)194-196 387 (CI) 40 N 2-methyl-piperidine^(g) 4-pyridine 4-fluoro2-methyl Ex 4 (56) 209-210(d) 430 (CI) 41 N 4-ketal-piperidine phenyl HH Ex 4 (52) 210-212 442 (CI) 42 N 1,2-tetrahydrooxazine phenyl 4-fluoro2-methyl Ex 4 (32) 199-200(d) 417 (CI) 43 N 2-methyl-piperidine4-fluoro- 4-fluoro 2,6- Ex 4 (56) 162-164 461 (CI) phenyl dimethyl (d)44 N 2-methyl-piperidine^(g) phenyl 4-fluoro 2,6- Ex 4 (44) 163-165 451(CI) difluoro (d) 45 N 2-methyl-piperidine phenyl 4-fluoro 2,6- Ex 4(58) 153-155 483 (CI) dichloro (d) 46 N 2-methyl-piperidine 4-chloro-4-fluoro 2,6- Ex 4 (79) 149-151 477 (CI) phenyl dimethyl (d) 47 N1-adamantine phenyl 4-fluoro 2-methyl Ex 11 (51) 219-221 465 (EI) 48 N2,6-dimethyl-piperidine phenyl 4-fluoro 2,6- Ex 4 (89) 172-174 457 (CI)dimethyl (d) 49 N hexamethyleneimine 4-fluoro- 4-fluoro 2,6- Ex 4 (74)155-157 461 (CI) phenyl dimethyl 50 N 1,2-tetrahydrooxazine 4-fluoro-4-fluoro 2,6- Ex 4 (29) 213-214 449 (CI) phenyl dimethyl 51 N2-methyl-piperidine^(g) 4-fluoro- 4-fluoro 2,6- Ex 4 (56) 171-173 469(CI) phenyl difluoro 52 N 2,6-dimethyl-piperidine^(g) 4-fluoro- 4-fluoro2,6- Ex 4 (56) 172-174 483 (CI) phenyl difluoro 53 N hexamethyleneiminephenyl 4-fluoro 2,6- Ex 4 (44) 243-245 443 (CI) dimethyl 54 N2,6-dimethyl-piperidine 4-fluoro- 4-fluoro 2,6- Ex 4 (82) 180-181 469(CI) phenyl dimethyl 55 N 2,6-dimethyl-piperidine^(g) phenyl 4-fluoro2,6- Ex 4 (62) 175-177 483 (CI) difluoro 56 N hexamethyleneimine^(g)phenyl 4-fluoro 2,6- Ex 4 (54) 171-173 451 (CI) difluoro 57 Nhexamethyleneimine 4-fluoro- 4-fluoro 2,6- Ex 5 (30) 216-218 469 (CI)phenyl difluoro 58 N 2-ethyl-piperidine phenyl 4-fluoro 2,6- Ex 5 (56)137-139 457 (CI) dimethyl (d) 59 N trans-2,6-dimethyl- phenyl 4-fluoro2,6- Ex 5 (67) 165-167 457 (CI) piperidine dimethyl (d) 60 N2-methyl-piperidine phenyl 4-methyloxy 2-methyl Ex 5 (77) 162-164 441(CI) (d) 61 N 1,2-tetrahydrooxazine phenyl 4-fluoro 2,6- Ex 5 (58)212-214 431 (CI) dimethyl (d) 62 N 3-hydroxy-piperidine phenyl 4-fluoro2,6- Ex 5 (53) 196-198 444 (EI) dimethyl (d) 63 N 4-keto-piperidinephenyl 4-fluoro 2,6- Ex 8 (65) 228-229 443 (CI) dimethyl (d) 64 N2-methyl-piperidine 4-NH₂- 4-fluoro 2,6- 179-181 phenyl dimethyl 65 N2-methyl-4-keto- phenyl 4-fluoro 2,6- Ex 8 (91) 215-217 457 (CI)piperidine dimethyl 66 N 3-hydroxy-piperidine phenyl 4-fluoro 2-methylEx 4 (50) >150 431 (CI) 67 N 1,2-tetrahydrooxazine phenyl 4-methoxy 2,6-Ex 5 (70) 214-215 443 (CI) dimethyl 68 N hexamethyleneimine phenyl4-methoxy 2,6- Ex 5 (48) 228-230 455 (CI) dimethyl (d) 69 N2-methyl-4-keto- phenyl 4-fluoro 2-methyl Ex 8 (87) >143 441 (CI)piperidine 70 N 2-methyl-piperidine 3-NH₂- 4-fluoro 2,6- Ex 7 (4)210-213 458 (CI) phenyl dimethyl 71 N 4-hydroxy-piperidine phenyl4-fluoro 2,6- Ex 9 (45) 163-165 445 (CI) dimethyl 72 N2-methyl-4-hydroxy- phenyl 4-fluoro 2,6- Ex 9 (33) 163-166 459 (CI)piperidine dimethyl (d) 73 N 2-methyl-piperidine 3-NH₂- 4-OCF₃ 2,6- Ex 7(11) 170-172 525 (CI) phenyl dimethyl 74 N 2-methyl-piperidine phenyl4-OCF₃ 2,6- Ex 7 (25) 148-150 510 (CI) dimethyl 75 N 2-methyl-piperidine2-methyl- 4-fluoro 2-methyl Ex 7 (17) 171-173 444 (CI) phenyl (d) 76 Nmorpholine phenyl 4-fluoro 2,6- Ex 5 (79) 249-251 431 (CI) dimethyl (d)77 N 2-methyl-piperidine 3-methyl- 4-fluoro 2,6- Ex 7 (16) 140-142 458(CI) phenyl dimethyl 78 N 2-methyl-piperidine 3-fluoro- 4-fluoro 2,6- Ex7 (25) 143-147 462 (CI) phenyl dimethyl 79 N 2-methyl-piperidine2-chloro- 4-fluoro 2-methyl Ex 5 (97) 208-210 462 (CI) phenyl 464 (CI)80 N 2-methyl-piperidine 2- 4-fluoro 2-methyl Ex 5 (80) 150-152 460 (CI)methoxy- phenyl 81 N 2-methyl-piperidine 3- 4-fluoro 2,6- Ex 3 (54)199-201 474 (CI) methoxy- dimethyl phenyl 82 N trans-2-methyl-4- phenyl4-fluoro 2,6- Ex 5 (54)^(d) 169-172 459 (EI) hydroxy-piperidine dimethyl83 N cis-2-methyl-4- phenyl 4-fluoro 2,6- Ex 5 (65)^(d) 165-167 460 (CI)hydroxy-piperidine dimethyl 84 N 2-methyl-piperidine 2-methyl- 4-fluoro2,6- Ex 5 (51) 206-208 457 (CI) phenyl dimethyl 85 N 2-methyl-piperidine2-chloro- 4-fluoro 2,6- Ex 5 (52) 207-209 477 (CI) phenyl dimethyl 86 N2-methyl-piperidine 3- 4-fluoro 2,6- Ex 5 (57)^(d) 207-210 444 (CI)pyridinyl dimethyl 87 CH pyrrolidine^(g) phenyl H H Ex 6 (41) 184-186368 (CI) 88 CH thiazolidine phenyl H H Ex 3 (10) amorphous 386 (EI) 89CH 2-methyl-piperidine^(g) phenyl 4-fluoro 2-methyl Ex 6 (76) 179-181428 (CI) 90 CH 2-methyl-piperidine^(g) phenyl 4-fluoro 2-chloro Ex 6(76) 152-155 448 (CI) 91 CH 1,2-tetrahydrooxazine^(g) phenyl 4-fluoro2-methyl Ex 6 (42) 151-153 416 (CI) 92 CH 2-methyl-piperidine^(g)4-fluoro- 4-fluoro 2-methyl Ex 6 (80) >90 (d) 446 (CI) phenyl 93 CH2-methyl-piperidine phenyl H H Ex 6 (60) 157-158 396 (CI) 94 CH1,2-tetrahydrooxazine phenyl 4-methoxy 2-methyl Ex 6 (24) 192-194 428(CI) 95 CH 1,2-tetrahydrooxazine cyclohexyl 2-fluoro 2-methyl Ex 6 (70)171-172 422 (CI) 96 N 1-methylcyclohexyl cyclohexyl 4-fluoro 2-methyl Ex11 (10) 127-129 433 (EI) 97 N 2-methyl-piperidine cyclohexyl 4-fluoro2-methyl Ex 7 (7) >160 (d) 435 (CI) 98 N 2-methyl-piperidine 2-butyl-4-fluoro 2,6- Ex 7 (30) 168-170 (d) 423 (CI) phenyl dimethyl 99 N2-methyl-piperidine 2-propyl- 4-fluoro 2,6- Ex 7 (32) 208-210 (d) 409(CI) phenyl dimethyl 100 CH 2-methyl-piperidine cyclohexyl 4-fluoro2-methyl Ex 4 (74) >125 (d) 434 (CI) 101 N 1-adamantine cyclohexyl4-fluoro 2-methyl Ex 11 (24) amorphous 471 (EI) 102 N2-methyl-piperidine cyclobutyl 4-fluoro 2,6- Ex 7 (12) 136-138 420 (EI)dimethyl 103 N 2-methyl-piperidine cyclopropyl 4-fluoro 2,6- Ex 7 (20)219-220 406 (EI) dimethyl 104 N 1,2-tetrahydrooxazine cyclopropyl4-fluoro 2,6- Ex 5 (40) 229-231 (d) 395 (CI) dimethyl 105 N2-methyl-piperidine cyclopropyl 4-fluoro 2-methyl Ex 7 (18) amorphous393 (CI) 106 N 1-methyl-cyclohexyl cyclopropyl 4-fluoro 2-methyl Ex 11(63) 205-207 391 (EI) 107 CH 1,2-tetrahydrooxazine cyclopropyl 4-fluoro2-methyl Ex 4 (70) 140-142 (d) 380 (CI) 108 N 2-methyl-piperidinecyclopropyl 4-methoxy 2,6- Ex 5 (78) 194-195 490 (CI) dimethyl 109 N2-methyl-piperidine cyclopropyl- 4-fluoro 2,6- Ex 7 (14) amorphous 420(EI) methyl dimethyl 110 CH 1,2-tetrahydrooxazine^(g) cyclopropyl4-fluoro H Ex 4 (35) 82-84 366 (CI) 111 N 2-methyl-piperidine allyl4-fluoro 2,6- Ex 7 (13) amorphous 406 (EI) dimethyl 112 N2-methyl-piperidine morpholinyl 4-fluoro 2,6- Ex 7 (3) 169-171 453 (CI)dimethyl 113 N 2-methyl-piperidine 1- 4-fluoro 2,6- Ex 7 (3) 170-172 451(CI) piperidinyl dimethyl 114 N 2-methyl-piperidine 2-methyl- 4-fluoro2,6- Ex 5 (47) 176-178 422 (CI) cyclopropyl dimethyl

1. A compound of the formula

wherein X is NR⁴R⁵, (C₁-C₁₀)alkyl or (C₃-C₁₀)cycloalkyl, wherein said(C₃-C₁₀)cycloalkyl may optionally be substituted with from one to threesubstituents independently selected from the group consisting of —OR⁶,(C₁-C₄)alkyl, oxo and a ketal of the formula —O—(CH₂)n—O—; n is aninteger from one to three; m is an integer from one to three; p is aninteger from one to three; Y is N or CH; Z is NR⁷R⁸, (C₃-C₁₀)cycloalkyl,(C₁-C₁₀)alkyl, pyridyl or phenyl; wherein said phenyl or(C₃-C₁₀)cycloalkyl may optionally be substituted with from one to threesubstituents independently selected from the group consisting of(C₁-C₆)alkyl, halo, hydroxy, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,di(C₁-C₆)-alkylamino and trifluoromethoxy; R² is phenyl optionallysubstituted with from one to three substituents independently selectedfrom the group consisting of (C₁-C₆)alkyl, halo, hydroxy, (C₁-C₆)alkoxy,amino, (C₁-C₆)alkylamino, di(C₁-C₆)-alkylamino, —CF₃, —CN, —CORR⁶,NHCOR⁶ and trifluoromethoxy; R³ is phenyl optionally substituted withfrom one to three substituents independently selected from the groupconsisting of (C₁-C₆)alkyl, halo, hydroxy, (C₁-C₆)alkoxy, amino,(C₁-C₆)alkylamino, di(C₁-C₆)-alkylamino and trifluoromethoxy; R⁴ and R⁵are independently (C₁-C₁₀)alkyl or R⁴ and R⁵ taken together with thenitrogen atom to which they are attached form a (five to nine)-memberedsaturated heterocyclic ring in which one of the ring atoms mayoptionally be replaced with a heteroatom selected from the groupconsisting of nitrogen, oxygen and sulfur, wherein said (five tonine)-membered saturated heterocyclic ring may optionally be substitutedwith from one to three substituents independently selected from thegroup consisting of —OR⁶, (C-C₄)alkyl, oxo and a ketal of the formula—O—(CH₂)_(m)—O—; with the proviso that said substituted heterocycles maynot be substituted next to a heteroatom by hydroxy or a ketal; R⁶ ishydrogen or (C₁-C₈)alkyl; and R⁷ and R⁸ are independently (C₁-C₁₀)alkylor R⁷ and R⁸ taken together with the nitrogen atom to which they areattached form a (five to seven)-membered saturated heterocyclic ring inwhich one of the ring atoms may optionally be replaced with a heteroatomselected from the group consisting of nitrogen, oxygen and sulfur,wherein said (five to seven)-membered saturated heterocyclic ring mayoptionally be substituted with from one to three substituentsindependently selected from the group consisting of —OR⁶, (C₁-C₄)alkyl,oxo and a ketal of the formula —O—(CH₂)_(p)—O—; with the proviso thatsaid substituted heterocycles may not be substituted in the two positionby hydroxy or a ketal; and the pharmaceutically acceptable saltsthereof.
 2. A compound according to claim 1, wherein Z is pyridyl, orphenyl optionally substituted with from one to three substituentsindependently selected from the group consisting of (C-C₆)alkyl, halo,hydroxy, (C₁-C₆)alkoxy, amino, (C₁-C₆,)alkylamino, di(C₁-C₆)-alkylaminoand trifluoromethoxy.
 3. A compound according to claim 2, wherein X isNR⁴R⁵ and R⁴ and R⁵ are taken together with the nitrogen atom to whichthey are attached to form an optionally substituted (five tonine)-membered saturated heterocyclic ring selected from piperidine,pyrrolidine, thiomorpholine, hexamethylenimine, morpholine, thiazolidineand 1,2-tetrahydrooxazine.
 4. A compound according to claim 3, wherein Xis an optionally substituted heterocycle selected from the groupconsisting of piperidine and 1,2-tetrahydrooxazine.
 5. A compoundaccording to claim 3, wherein R² is phenyl optionally substituted withhalo, hydroxy or methoxy.
 6. A compound according to claim 4, wherein R²is phenyl optionally substituted with halo, hydroxy or methoxy.
 7. Acompound according to claim 6, wherein R² is phenyl substituted in the4-position of the phenyl ring with fluoro or methoxy.
 8. A compoundaccording to claim 3, wherein R³ is phenyl substituted with twosubstituents independently selected from (C-C₆)alkyl, halo, hydroxy,(C-C₆)alkoxy, amino, (C₁-C₆)alkylamino, di(C₁-C₆)-alkylamino andtrifluoroalkoxy.
 9. A compound according to claim 4, wherein R³ isphenyl substituted with two substituents independently selected from(C₁-C₆)alkyl, halo, hydroxy, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,di(C₁-C₆)-alkylamino and trifluoroalkoxy.
 10. A compound according toclaim 6, wherein R³ is phenyl substituted with two substituentsindependently selected from (C₁-C₆)alkyl, halo, hydroxy, (C₁-C₆)alkoxy,amino, (C₁-C₆)alkylamino di(C₁-C₆)-alkylamino and trifluoroalkoxy.
 11. Acompound according to claim 4 wherein said piperidine is substituted inthe two position with (C₁-C₄)alkyl.
 12. A compound according to claim 8wherein said piperidine is substituted in the two position with(C₁-C₄)alkyl.
 13. A compound according to claim 10 wherein saidpiperidine is substituted in the two position with (C₁-C₄)alkyl.
 14. Acompound according to claim 11, wherein R³ is 2,6-dimethylphenyl.
 15. Acompound according to claim 12, wherein R³ is 2,6-dimethylphenyl.
 16. Acompound according to claim 13, wherein R³ is 2,6-dimethylphenyl.
 17. Apharmaceutical composition for treating or preventing a disease orcondition, the treatment or prevention of which can be effected orfacilitated by enhancing cholinergic neurotransmission in a mammal,comprising a muscarinic receptor binding effective amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 18. A method of treating orpreventing a disease or condition, the treatment or prevention of whichcan be effected or facilitated by enhancing cholinergicneurotransmission in a mammal, comprising administering to said mammal amuscarinic receptor binding effective amount of a compound according toclaim 1 or a pharmaceutically acceptable salt thereof.
 19. Apharmaceutical composition for treating or preventing a disease orcondition, the treatment or prevention of which can be effected orfacilitated by enhancing cholinergic neurotransmission in a mammal,comprising administering to said mammal an amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof thatis effective in treating or preventing such condition.
 20. A method oftreating or preventing a disease or condition, the treatment orprevention of which can be effected or facilitated by enhancingcholinergic neurotransmission in a mammal, comprising administering tosaid mammal an amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof that is effective in treatingor preventing such condition.
 21. A method of treating, preventing ordiagnosing a disease or condition selected from the group consisting ofpsychotic disorders, pain, sleep disorders, depression, Alzheimer'sdisease, tardive dyskinesia, Picks disease, Huntington's chores,Friederich's ataxia, Gilles de la Tourette's disease, Down's Syndrome,attention-deficit disorder, multi-infarct dementia, and age-relatedcognitive decline (ARCD) in a mammal, comprising administering to amammal in need of such treatment, prevention or diagnosis an amount of acompound according to claim 1 effective in treating, preventing ordiagnosing such condition.
 22. A pharmaceutical composition fortreating, preventing or diagnosing a disease or condition selected fromthe group consisting of psychotic disorders, pain, sleep disorders,depression, Alzheimer's disease, tardive dyskinesia, Picks disease,Huntington's chorea, Friederich's ataxia, Gilles de la Tourette'sdisease, Down's Syndrome, attention-deficit disorder, multi-infarctdementia, and age-related cognitive decline (ARCD) in a mammal,comprising an amount of a compound according to claim 1 effective intreating, preventing or diagnosing such condition and a pharmaceuticallyacceptable carrier.